Cancer Research Frontiers. 2017; 3(1): 126-143. doi: 10.17980/2017.126 Review

Review Peptidyl-prolyl (PPIase): an emerging area in tumor biology Pulak Ranjan Nath1* 1Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

*Corresponding author: *Corresponding author: Dr. Pulak Ranjan Nath, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20812, USA. Tel:+1 (301) 480 4353, Fax:+1 (301) 480 0611; E-Mail: [email protected] or [email protected] Citation: Pulak Ranjan Nath. Peptidyl- (PPIase): an emerging area in tumor biology. Cancer Research Frontiers. 2017; 3(1): 126-143. doi: 10.17980/2017.126 Copyright: @ 2017 Pulak Ranjan Nath. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Competing Interests: The author declares no competing financial interests. Received May 5, 2017; Revised Sept 10, 2017; Accepted Oct 2, 2017. Published Nov 6, 2017 Abstract Peptidyl-prolyl isomerase (PPIase) catalyzes the interconversion of a specific Pro-imide bond between the cis and trans conformations. Such conformational interconversion by PPIases at the backbone of key signaling proteins is an emerging area of active research. Two families of PPIases, and FK506-binding proteins (), have been extensively studied due to their high affinity for immunosuppressive drugs, cyclosporine A and FK506, respectively. These two families of PPIases and also Pin1 within the -family mediate temporal and spatial conformational modifications of signaling proteins; therefore, affecting the downstream signaling events. PPIases have recently been implicated in multiple aspects of cycle regulation and cellular processes related to a number of human pathologies, including cancer. This review highlights the causal relationship between PPIases and malignant transformation and progression. Based on the current understanding, it is postulated that a cancer intervention strategy based on the development of isomerase-specific inhibitors is not far away. Keywords: PPIases, , FKBP, Pin1 Posttranslational protein modifications not only increase in the diversity of the proteome, but serve Introduction also as efficient mechanisms for temporal and spatial A properly folded protein under physiological regulation of activity in many types of effector conditions must maintain its functional integrity as a molecules. Among the most common mechanisms of part of the entire proteome. Pathophysiological protein modifications, peptidyl-prolyl cis–trans alterations, such as malignancy, have been shown to isomerization, mediated by a family of remodel folding-mediated signaling pathways. termed as PPIases, has been a topic of active research. Typically, certain peptide bonds on the backbone of a PPIase includes a large number of highly conserved native protein can adopt cis/trans isomerism, which proteins, which are widely distributed throughout resembles a molecular switch for bioactivity (1). Any organisms. These are structurally related proteins and alteration of the productive folding and restructuring share an isomerization domain [Fig. 1]. PPIases are pathways may result in misfolded and dysfunctional also found to be overexpressed in a variety of human proteins that are implicated to play critical role in tumors [Fig. 2, Table 1], and are implicated to play malignancy (2). Distinct posttranslational modification critical role in tumor generation and progression. mechanisms involving a large number of proteins The unique property of PPIases (EC 5.2.1.8) attributes tightly regulate cell growth and differentiation. to their ability to modify protein structure by cis–

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Table 1. List of human cancers that exhibit overexpression of specific family of PPIases.

Cyclophilins Ref. FKBPs Ref. Pin1 Ref.

Glioma 50 CLL 71 Melanoma 112,113 Myeloma 49 Glioma 84 Lung cancer 107,112,113 Melanoma 57 Melanoma 85,89 Ovary cancer 112,113 Lung cancer 34 Astrocytoma 70 Breast cancer 112,113 Brain tumor 34 Glioblastoma 27, 73 Cervical tumor 112,113 Breast cancer 34,53 Breast cancer 95,96,105 Oral carcinoma 98,110,111 Uterus cancer 53 Retinal tumor 90 Prostate cancer 108,109 Ovarian cancer 53 Prostate cancer 53,101 Esophageal 110 Prostate cancer 39,53 Colorectal cancer 102 carcinoma Adenocarcinoma 42 Cervical neoplasia 78 Esophageal cancer 43 B-cell lymphoma 75 Endometrial carcinoma 36 Epithelial carcinoma 82 Hepatocellular 34,40 Hepatocellular carcinoma 99 carcinoma

trans-isomerization of peptide bonds preceding to a enzymatic domains [Fig. 1], suggesting a broad specific residue. Though, a trans (ω = 180◦) substrate specificity and functional redundancy (21). conformation is energetically favored, below 10% of Cyps and FKBPs, also known as ‘’, have the newly synthesized proteins containing a peptidyl- high binding affinity for the immunosuppressive drugs prolyl bond, acquire a cis (ω = 0◦) conformation during cyclosporine A (CsA) and FK506, respectively (22). normal physiological processes in the . The Immunophilins were initially identified as molecular high-energy barrier between the cis and trans states chaperones (20) though their isomerization-based role (3) mostly limits a spontaneous cis–trans protein in folding of nascent proteins was appreciated. interconversion (4-6). Thanks to an active PPIase, Immunophilins interact with calcineurin at the basal which greatly reduces the free energy requirement level, however the affinity of such interaction and accelerates the interconversion of protein states increases upon binding of CsA and FK506. (7-9) and results in more biologically meaningful Immunophilin-calcineurin interaction results in the consequences. Recently, we have shown that PPIases inhibition of calcineurin to activate NF-AT (23) and play important role in T cell signaling pathways by subsequent transcription of the IL-2 gene (24) altering conformational regulation of adaptor protein CrkII survival and differentiation of CD4+ and CD8+ T cells (10-12). However, controversies on the true catalytic (25). We have recently discussed the molecular mechanism driving cis–trans isomerization are still pathways that are affected by the CsA-Cyp and FK506- prevalent (13-17). FKBP interactions elsewhere (21). Members of the PPIases are grouped into three subfamilies: third subfamily of PPIases, parvulins including Pin1, cyclophilins (Cyps), FK506 binding protein (FKBPs), and are structurally and functionally distinct from Cyps or parvulins (18-20). We have recently listed several FKBPs. Unlike the immunophilins, the catalytic activity distinct functional proteins of Cyps, FKBPs and of Pin1 is kinase activation-dependent and isomerizes parvulins that play an important role in immune cells, phospho-serine/threonine-proline motif-containing cellular localization and chromosomal locations of proteins. The role of immunophilins and Pin1 in the encoding genes (21). We found that the prototypic regulation of immune cell functions and their members of PPIase families, CypA, FKBP12 and Pin1 involvement in the regulation of other normal and are ubiquitously expressed in mouse organs and pathological cellular functions have recently been tissues [Fig. 3]. Interestingly, members of three discussed elsewhere (21,26-29). This review takes a families of PPIases share conserved regions within

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Cancer Research Frontiers. 2017; 3(1): 126-143. doi: 10.17980/2017.126 Review

Schematic Schematic

n n numbers

that that are involved in tumor growth

dues that border the protein domains or modules modules or domains protein the border that dues

member member proteins

-

recognition recognition motif; TPR, tetratricopeptide repeat; EF, EF hand; WD40,

Prot, Pfam or ClustalW alignment. The PPIase domain is indicated in red. Functionally important important Functionally red. in indicated is domain PPIase The alignment. ClustalW or Pfam Prot,

-

Prot database and NCBI Reference Sequence are given. resi acid Amino given. are Sequence Reference NCBI and database Prot

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Figure 1. Schematic representation of structures of PPIases playing important roles in tumor development and progression. diagrams depicting structures of the of selective cyclophilin, FKBP and purvulin family and metastasis. Sizes of the unprocessed protein are shown in brackets next to the gene name. In the second row, the accessio UniProtKB/Swiss of UniProtKB/Swiss to according designated are amino acid residues of Cyps, FKBPs and Pin1 are indicated. rrm, RNA WD40repeat.

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Figure 2. Expression profiles of the prototypic members cyclophilin, FKBP and parvulin family across various types of human tumors. Staining profiles for CypA, FKBP12 and Pin1 in human tumor tissues based on immunohistochemisty using tissue micro arrays and archived from The Human Protein Atlas (http://www.proteinatlas.org). Each bar represents data from at least 10 patient samples.

close look into the connections between PPIases and involves, but not limited to, muscle differentiation, tumor generation and progression. detoxification of reactive oxygen species (ROS) (34) and immune response (21). The nuclease activity of Cyclophilins and malignancies Cyps is similar to apoptotic endonucleases implicated Cyclophilins (Cyps) are the intracellular ligands for the by their function to apoptotic DNA degradation. immunosuppressive drug cyclosporine A (CsA). They Secreted Cyps, e.g. CypA, are present in human serum function as molecular chaperones for proper folding of in nanomolar range, which is elevated during proteins and also catalyze isomerization of peptide inflammatory diseases (35). Extracellular CypA bonds preceding proline (30-32). Cyps are highly promotes chemotactic activity of leucocytes by conserved proteins throughout evolution. There are interacting with its major signaling receptor CD147 around 20 putative genes of Cyps distributed (36). Such interaction in macrophages promotes throughout the human genome that encode a total of development of rheumatoid arthritis within the about 16 Cyp proteins in humans (21,33). Cyp proteins synovium (37). Similarly, CypA deficient mice had are localized in specific cellular compartments limited recruitment of inflammatory cells (CD45+) in including the cytosol, endoplasmic reticulum (ER), the cardiovascular wall (38). Secreted CypA plays mitochondria and nucleus and show specific important role for vascular inflammation and pathological significance (21). Their physiological role pathogenesis in diabetic patients (39). Cyps also play

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Figure 3. Protein expression profile of the prototypic members of cyclophilin, FKBP and parvulin family across various organs and tissues of mice. Lysates from organs and tissues of eight weeks-old C57BL/6 male mice were prepared and 30 μg proteins per lane were subjected to SDS-PAGE. Proteins were then electroblotted onto nitrocellulase membrane and CypA, FKBP12 and Pin1 proteins were visualized using specific Abs reactive against mouse proteins after sequential stripping and blotting (panels A, B & C). Reblotting of the stripped membrane with mouse mAb anti-Actin was performed as a protein loading control (panel D). Immunoreactive protein bands were detected using HRP-conjugated secondary Abs and immunoperoxidase ECL detection system, followed by autoradiography. Results are representative of three independent experiments.

important roles in viral infection in the host. CypA is types exhibited an elevated expression of CypA incorporated into viral particles and either increases compared to normal tissue samples (45). The HIV and vaccinia virus infectivity (40,41) or suppresses prototypic CypA is indicative of malignant rotavirus and influenza virus (42,43). Cyps are also well transformation (44), and thus has been suggested to documented among the major overexpressed proteins be a prognostic marker (46) for tumor formation. In a in multiple types of cancer; however, their precise role clinical study, treatment of female patients who were in cellular transformation is not well defined. chronically immunosuppressed with CsA in combination with other drugs, showed a surprisingly CypA low incidence of de novo breast cancers (47). Cyclophilins have been found to be associated with a Regulation of the prolactin receptor (PRLr)/ Janus variety of cancer types including lung, breast, liver, and kinase 2 (Jak2) complex by CypA has been shown to prostate (44). Extended CypA mRNA expression decrease the risk of female breast cancer. PRL induced profiling performed by serial analysis of gene expression of the transcription factor STAT5 was expression indicated that over 80% of cancer tissue directly correlated to the level of intracellular CypA

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(48). CypA is also overexpressed in pancreatic cancer (61). CypD is also significantly upregulated in ovarian cell lines and in human pancreatic adenocarcinoma as cancer (62), breast cancer (62), uterus cancer (62) and compared to normal tissues. Exogenous addition of prostate cancer (63). Cyp33 is significantly CypA significantly stimulated cancer cell proliferation upregulated in glioblastoma compared to non- (49). CypA was also identified as a novel hepatocellular neoplastic brain tissue (64). Peptidyl prolyl cis-trans carcinoma marker that was overexpressed in patient- isomease-like protein1 (PPIL1) is overexpressed in derived tissue, compared to normal counterparts (50). patient-derived colon cancer tissue, and siRNA As expected, siRNA mediated suppression of CypA in mediated suppression of PPIL1 in the human colon cell non-small cell lung tumor resulted in reduced cell line SNUC4 suppressed cell growth (65). Interaction of growth (51). CypA is also overexpressed in metastatic androgen receptor with Cyp40 and FKBP51 melanoma (52), gastric adenocarcinoma (53) and in augmented androgen-dependent prostate cancer and clinical endometrial carcinoma specimens (46). treatment of prostate cancer cell lines with CsA and FK506 consequently inhibited androgen-dependent The hypoxia-inducible factor 1α (HIF1-α) (54) and the cell growth and gene transcription (63). The tumor suppressor p53 are involved in CypA combination of sanglifehrin and CsA, two potent overexpression or exosome-mediated CypA secretion inhibitors of most cyclophilin isoforms, synergistically in various cancer cells. CypA physically and increased apoptotic cell death. Decreased cyclophilins functionally interacts with p53 by limiting its DNA in hepatocellular carcinoma (HCC) and glioma cell lines binding ability and enhancing the anti-apoptotic induced apoptosis, indicating that these PPIases are cellular responses (55). essential in tumorigenesis (56,57). Studies CypB investigating the involvement of various Cyp isoforms CypB is also implicated in the proliferation and survival may help explain the synergism between the of breast, liver, brain, and myeloma cancer. siRNA reduction of Cyps and apoptosis induction. mediated repression of CypB in ductal breast epithelial Cyps and chemoresistance tumor cells decreased cell growth, proliferation and Cyclophilins are also associated with cancer motility (58). CypB is found to interact with the chemoresistance. For example, overexpression of transcription factor STAT3 in HepG2 liver cells and CypA is associated with resistance of prostate cancer inhibition of CypB in STAT3-dependent human cells to cisplatin-induced cell death. It is proposed that myeloma cell lines resulted in apoptosis, suggesting CypA suppresses cisplatin-induced ROS production that CypB acts as a pro-survival protein in these cells and the loss of mitochondrial membrane potential (59). CypB is also overexpressed in malignant glioma (54). Consistent with that finding, loss of CypA tissue and suppression of CypB resulted in reduced cell expression was found to increase mitochondrial growth and increased mortality in vitro and in vivo membrane depolarization and reduce survival (60). following H2O2 treatment (54). CypA is down regulated CypB-STAT3 interaction was found to be of low affinity in melphalan-resistant MCF7 breast cancer cells when in multiple myeloma cells. Administration of CsA in compared to non-resistant cells (66). This down multiple myeloma cells led to apoptotic cell death of regulation of CypA allows evasion of apoptosis in these cells. A catalytically compromised CypB mutant MCF7 by inhibition of apoptosis-inducing factor (AIF) did not show any effect on STAT3 transcriptional (67). Furthermore, CypA-overexpressing endothelial activity, suggesting that CypB requires its PPIase liver cells display resistance to doxorubicin and activity to act on STAT3 (59). vincristine (68). CypA is also overexpressed in Other Cyps endometrial cancer cells, HEC-1-B/TAX and AN3CA/TAX, and promotes cellular resistance to CypC overexpression in circulating tumor cells after paclitaxel. siRNA-mediated knockdown of CypA chemotherapy is associated with poor survival of significantly inhibited cell proliferation and invasion ovarian cancer patients and has been identified as a upon treatment with paclitaxel. Mechanistic novel gene marker for detecting circulating tumor cells investigation revealed that paclitaxel treatment of

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CypA deficient endometrial cancer cells reduces astrocytomas showed that the protein level of FKBP12 phosphorylation of Akt and the MAPK ERK1/2, p38 and was associated with increased expression of hypoxia- JNK suggesting that overexpression of CypA enhances inducible transcription factor (HIF)-2α and epidermal MAPK activity (69). growth factor receptor (EGFR) in malignant high-grade astrocytomas. Among multiple FKBPs that were highly Under hypoxic conditions, HIF-1α upregulates CypB in expressed in astrocytoma cells, FKBP12 appeared to human hepatocellular carcinoma. Knockdown of CypB have a pathogenetic role in tumor aggressiveness. significantly reduced cell survival when subjected to FKBP12/HIF2/EGFR was involved in angiogenesis of hypoxia, cisplatin, or H2O2 treatment (70), suggesting childhood high-grade astrocytomas, suggesting that that CypB may play a similar role to CypA in cisplatin these genes may represent a potentially new resistance by protecting the cells against ROS induced therapeutic target. stress (54). Moreover, the role of some PPIases in tumor progression strictly correlates with their FKBP12 mediates the ability of chronic lymphocytic subcellular localization. Expression of CypD, for leukemia (CLL) cells to escape from the homeostatic example, is restricted to mitochondria and is directly control of TGF-β (81). FK506 has been shown to involved in resistance to apoptotic stimuli through reactivate the TGF-β signal in CLL, and induce regulation of the mitochondrial permeability apoptosis through the mitochondria-dependent transition pore (71). These studies confirm that pathway in 33 out of 62 patient samples. FKBP12 acts upregulation of cyclophilins is associated with tumor as a natural ligand for the TGF-β type I receptor (TβR- progression, acquired chemoresistance and resistance I) (82). Association of FKBP12 with TβR-I is via a to apoptosis. Cyclophilins may therefore represent glycine- and serine-rich motif of TβR-I, which caps its valuable biomarkers for chemoresistance and phosphorylation and stabilizing its inactive potential therapeutic targets to sensitize cancer cells conformation of TβR-I. The PPIase core domain of to chemotherapy. FKBP12 is important for the interaction of the immunophilin with TβR-I. FK506 inhibits this FKBPs and malignancies interaction and promotes receptor trans- Like Cyps, FKBPs also function as molecular autophosphorylation (82), which in resulted in chaperones and catalyze the Pro-imide bonds. FKBPs apoptosis of both normal and leukemic lymphocytes. of bacterial origin can activate mitogenic signaling FKBP24 pathways, ERK and EGF-R, upon infection of gastric epithelial cells and promote cellular transformation FKBP24, a molecule downstream to EGFR signaling (72). FKBPs are mostly known as cellular targets for pathway, was identified in glioblastoma and as FK506 and Rapamycin. FK506 and Rapamycin gained molecular determinant responsible for resistance of attention over the last decade as anti-cancer glioblastoma to Erlotinib, a small molecule inhibitor of immunosuppressant agents (73-75). Both drugs are EGFR tyrosine kinase activity (83). widely used following organ transplantation for FKBP25 preventing allograft rejection. The FK506-FKBP complex inhibits calcineurin phosphatase activity and FKBP25 was identified as a transcriptional target of Rapamycin-FKBP complex inhibits mTOR activity. Both Multiple Myeloma Oncogene 1/ Interferon Regulatory calcineurin (75-77) and mTOR (73,74,78) are Factor 4 (MUM1/IRF4) (84). Increased MUM1 implicated in tumor growth and metastasis. There are expression was observed in various B-cell lymphomas about 15 putative genes of FKBPs distributed and predicts an unfavorable outcome in some throughout the human genome that encode a total of lymphoma subtypes (85). at least 16 proteins with molecular weight ranging FKBP25 stimulated auto-ubiquitylation and from 12 to 133 kDa (21,79). proteasomal degradation of mouse double minute 2 FKBP12 homolog (MDM2), leading to the induction of p53 and its downstream effector p21 (86). On the other hand, FKBP12 is highly expresssed in childhood astrocytoma FKBP25 levels were decreased by p53 activation. This (80). The expression profiles of 13 childhood

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Cancer Research Frontiers. 2017; 3(1): 126-143. doi: 10.17980/2017.126 Review finding is in line of reduction of FKBP25 levels in both binding in prostate cancer cell line LNCaP and prostate human and murine immortalized and transformed cell tumor tissue (97). Periyasamy et al. found that FKBP51 lines following induction of wild-type p53 by several was upregulated in prostate cancer in association with DNA damaging stimuli (87). cyclophilin Cyp40 (63). Expression of FKBP51 in androgen-dependent tumor cell lines directly FKBP36 correlated with androgen-dependent transcriptional FKBP36 promoter is frequently methylated in cervical activity, while knockdown of FKBP51 dramatically neoplasia (88). This PPIase forms complexes decreased androgen-dependent gene transcription composed of piRNAs and Piwi proteins and govern the and proliferation (63). methylation and subsequent repression of FKBP51 regulates the anti-apoptotic effects in transposons that repress transposable elements and leukemia (98), melanoma (99), glioma (94), prostate prevent their mobilization, which is essential for the cancer (63) and retinal tumors (100). This is also germ-line integrity (89). necessary for chemotherapy (98,101), radiotherapy FKBP37 (99) and induction of NF-κB transcription factor, which The aryl hydrocarbon receptor (AHR) interacting in turn promoted transcription of anti-apoptotic protein AIP, also known as FKBP37, displays structural proteins and induced autophagy (99). similarity to FKBP52 but has distinct cellular roles. In The metastatic potential of melanoma positively pituitary adenoma, AIP gene functions as a tumor- correlates with the FKBP51 level (102). An interaction suppressor gene (90). Germline AIP result in between p300 and FKBP51 suggested that the the occurrence of large pituitary adenomas that occur immunophilin participated to chromatin remodeling at a young age, predominantly in events. Additionally, FKBP51 increased the tumor children/adolescents. Around 75% of AIP mutations promoter potential of the TGF-β (103). completely disrupt the C-terminal TPR domain, leading A tumor suppressor role for FKBP51 in pancreatic to failure of protein–protein interactions, a cancer has recently been suggested. FKBP51 acts as a mechanism appeared to be sufficient to predisposition scaffold for the phosphatase PHLPP, facilitating Akt de- to pituitary adenoma (91). phosphorylation in vitro, and favoring apoptotic FKBP38 response to gemcitabine (104). FKBP38 exerted an anti-apoptotic effect on epithelial FKBP52 carcinoma HeLa cells. Mechanistic investigation FKBP52, along with Cyp40, is highly expressed in revealed that FKBP38 anchors Bcl-2 and Bcl-xL to breast cancer cell lines (105). Data showed that mitochondria and protect mitochondria from FKBP52 was among the highest expressing proteins in induction of permeability transition (92). The authors breast cancer stem cells (106). Another study by Yang found that overexpression of FKBP38 prevented HeLa et al. suggested that FKBP52 is a biomarker for cells from apoptosis. Consistently, functional predictive breast cancer response to doxorubicin inhibition of FKBP38 by a dominant- negative mutant (107). or RNA interference promoted apoptosis (92). Both, mRNA and protein expression of FKBP52 was FKBP51 found to be elevated in early-stage breast tissues, such FKBP51 has been well documented in cancer growth as ductal in situ breast tumors in a clinical study and aggressiveness (93). In glioma (94), prostate including 60 early-stage primary breast cancers, 82 in cancer (63) and melanoma (95), a strict correlation situ breast carcinomas and 93 healthy controls. The between the tumor hostility and protein abundance authors also found FKBP52 auto-antibodies were has been demonstrated. Overexpression of FKBP51 associated with early stage breast cancer and increased androgen signaling in cells and contributes hypothesized that FKBP52 immunogenicity could be to prostate carcinogenesis (96). FKBP51 physically attributed to the increased protein expression (108). associates with the androgen receptor before ligand

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A study on the protein expression profile in the livers patients. Mechanistically, FKBPL promotes breast of tumor-prone transgenic mouse models of HCC cancer sensitivity to endocrine therapies and improve identified FKBP52 as a differentially expressed protein outcomes (115,116). (109). Levels of FKBP52 in serum samples appeared to Pin1 and malignancies be increased in HCC, compared with control cases. The regulation of FKBP52 was also found to be relevant to Expression of Pin1 increases in lung cancer and is HCC staging, with a dramatic decline at stage III. The associated with poor prognosis (117). Pin1 levels are study points out FKBP52 may be a biomarker for early found to be high in prostate tumor specimens after HCC diagnosis (109). prostatectomy and correlates with a higher probability of tumor recurrence (118,119). Such correlation with FKBP65 high Pin1 levels and disease progression has also been High expression of FKBP65 has been observed in found in non-small cell lung cancer and oral squamous benign tumor cells and in ovarian epithelium; cell carcinoma patients (117,120,121). High expression however, decreased in ovarian cancer cells (110). of Pin1 in esophageal squamous cell carcinoma FKBP65 is overexpressed in tumors harboring correlates with lymph node metastasis and is an rearrangements of the ETS (E26 transformation- independent prognostic factor for this disease (120). specific) transcription factor in prostate cancer (111). In a broad range analysis of 60 different human tumor Since it’s an active player in gene fusion, ETS factors types, 38 tumors including prostate, breast, lung, have been often found to be associated with cancer. ovary and cervical tumors, and melanoma have Pin1 The authors proposed that FKBP65 could serve as overexpression in more than 10% of cases compared diagnostic markers for molecular cancer subtypes in to the corresponding normal tissues (122,123). In prostate cancer harboring the ETV1 fusion gene addition, Pin1 expression has been found to correlate rearrangements. with other tumor markers such as β-catenin accumulation in oral squamous cell carcinoma and Olesen et al. identified FKBP65 as a novel marker cyclin D1 levels in esophageal and oral squamous cell associated with colorectal cancer (112). Analysis of 31 carcinoma (120,124,125). Pin1 antagonists, like colorectal adenocarcinomas showed a significant up- Juglone, PiB, dipentamethylenethiuram monosulfide regulation of FKBP65 in tumors, compared to normal and halogenated phenylisothiazolone TME-001, have colorectal mucosa. Moreover, immunohistochemical been found either to inhibit the PPIase activity of Pin1 analysis of 26 adenocarcinomas and matching normal or to target the Pin1 WW domain and preventing mucosae showed that FKBP65 was not present in binding of Pin1 to its substrates (126). Elevated levels normal colorectal epithelial cells, but highly expressed of Pin1 in tumors provide a therapeutic opportunity to in colorectal cancer cells. utilize these inhibitors against tumor development. FKBPL However, Pin1 may have a general regulatory role in Being a divergent member of FKBP family, FK506- healthy cells and therefore the specificity of these binding protein-like (FKBPL) shares homology within antagonists is still in question. More directed the TRP domain with FKBP52/51, however, contains a preclinical and clinical studies are required before weaker PPIase domain (113,114). Radiation promotes employing these inhibitors in humans. FKBPL protein binding to p21 and prevents its Mechanistically, Pin1 influences multiple signaling proteasomal degradation. Knock down of FKBPL pathways in malignant transformations. Studies in presumably reduces p21 and confers resistance to genetically depleted mouse models revealed varying radiation (113). FKBPL is also found to interact with roles of Pin1 in cancer depending on organ, tissue, age estrogen receptor alpha (115,116). Breast cancer cells and genetic background. Pin1 stabilizes cyclin D1 stably overexpressing FKBPL become highly sensitive proteins and regulates transcription factors c-Jun and to anti-estrogens tamoxifen and fulvestrant, whereas NF-kB within the cytoplasm. In addition, Lu and Zhou FKBPL knockdown reversed this phenotype. FKBPL precisely discussed the roles of Pin1 to activate certain expression correlates with increased overall survival and distant metastasis-free survival in breast cancer

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Cancer Research Frontiers. 2017; 3(1): 126-143. doi: 10.17980/2017.126 Review oncogenes and inactivate other important tumor level. The high abundance of PPIases in most human suppressors (127). tumor types [Fig. 2, Table 1] indicates their unique regulation in tumor biology. Overexpression of Pin1 also regulates the Ras-signaling pathways in multiple PPIases in individual cancer types indicates transformed mammary epithelial cells (128). Ras- their compensatory role and therefore may be induced focal adhesion kinase (FAK)- phosphorylation challenging for a designing therapeutic strategy with a at a serine residue leads to Pin1 recruitment to FAK. single agent. The involvement of PPIases in the Pin1 PPIase activity is required for dephosphorylation pathophysiological signaling processes in multiple of FAK at the tyrosine 397 residue by the protein cancers continues to be in the focus of biomedical tyrosine phosphatase PTP-PEST. Subsequently, research. Increasing clinical evidence of adverse inhibition of FAK activity promotes cell migration, effects including malignancies on transplanted invasion and Ras-induced metastasis (129). patients under CsA and FK506 treatment indicate a Additionally, Pin1 associates with Smad2 and Smad3 correlation with PPIase inhibition. The molecular and are phosphorylated in response to TGF-β. Pin1 mechanisms regulating the overexpression of activity was shown to be required for the reduction of different PPIases in tumors therefore need to be Smad2/3 protein levels (130). Interestingly, Pin1 was thoroughly examined in order to design common shown to promote migration and invasion of prostate therapeutic intervention. The non- cancer cells induced by TGF-β (131). immunosuppressive PPIase inhibitors as well as small Other tumorigenesis-specific Pin1 substrates include molecule inhibitors will facilitate future studies to Notch1 and p53 (132,133). Pin1 was found to interact dissect potential redundancies of cyclophilins, FKBPs with the phosphorylated Ser/Thr-rich region of Notch1 and Pin1 in tumorigenesis. enhancing its transcriptional activity and promoting tumourigenesis. γ-secretase, which cleaves Notch1 and activates downstream signaling pathways, was Acknowledgment found to be a Pin1 substrate. Combined inhibition of I am thankful to Dr. Anthony Schwartz for excellent γ-secretase and Pin1 significantly impaired tumor editorial assistance. I acknowledge the ‘Kreitman growth in a breast cancer xenograft model (133). Graduate Fellowship’ for supports during the doctoral Finally, Pin1 also acts on the conformational research at the Ben-Gurion University, Israel. The modification of p53 and upon phosphorylation after author is also a recipient of the ‘PBC Outstanding DNA damage it enhances transactivation activity Postdoctoral Fellowship’ and is thankful to the (134). Planning and Budgeting Committee (PBC), Council for Higher Education, Israel. I also thank Dr. Noah Isakov

for his supports during the course of this study. Conclusions

Despite providing a congenial microenvironment for Conflict of interest proper folding of a protein, the active participation in inducing conformational changes of a protein by The author declares no conflict of interest. PPIases is lately appreciated. Though, encoded by distinct genes from different locus, the isomerase domains of PPIases highly resemble their structural and functional traits. The multifunctional nature of Abbreviations PPIases is evident from their unique overall structures, ubiquitous presence and abundant distribution in AHR: Aryl hydrocarbon receptor; cells, indicating that isomerization is a critical process AIF: Apoptosis-inducing factor; in sustaining cellular maintenance machinery. PPIases Akt: serine/threonine-protein kinase; are bioactive and confer “on”/“off” - Bcl-2: B-cell lymphoma 2; based switches to their substrates, which undergo a Bcl-xL: B-cell lymphoma-extra large; functionally relevant structural change on a one-bond CLL: Chronic lymphocytic leukemia;

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CsA: Cyclosporine A; mTOR: mechanistic Target of rapamycin; Cyp: Cyclophilin; MUM1: Multiple Myeloma Oncogene 1; EGFR: Epidermal growth factor receptor; NF-AT: Nuclear factor of activated T cell; ER: Endoplasmic reticulum; Notch1: Notch homolog 1, translocation-associated; ERK: Extracellular signal–regulated kinase; PHLPP: PH domain and Leucine rich repeat Protein ETS: E26 transformation- specific; Phosphatases; ETV1: ETS translocation variant 1; PPIase: Peptidyl-prolyl cis/trans isomerase; FAK: Focal adhesion kinase; PPIL1: Peptidyl prolyl cis-trans isomease-like protein1; FKBPs: FK506-binding proteins; PRLr: Prolactin receptor; HCC: Hepatocellular carcinoma; PTP-PEST: Protein tyrosine phosphatase containing a HIF1-α: Hypoxia-inducible factor 1α; C-terminal PEST motif; IL-2: 2; ROS: Reactive oxygen species; IRF4: Interferon Regulatory Factor 4; STAT3/5: Signal transducer and activator of Jak2: Janus kinase 2; transcription 3/5; JNK: c-Jun N-terminal kinases; TGF-β: Transforming growth factor beta; MAPK: Mitogen-activated protein kinase; TPR: Tetratricopeptide repeat; MDM2: Mouse double minute 2 homolog; TβR-I: TGF-β type I receptor.

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