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Inhibition of Isoprenylcysteine Carboxylmethyltransferase Induces Published OnlineFirst February 6, 2017; DOI: 10.1158/1535-7163.MCT-16-0703 Cancer Biology and Signal Transduction Molecular Cancer Therapeutics Inhibition of Isoprenylcysteine Carboxylmethyltransferase Induces Cell-Cycle Arrest and Apoptosis through p21 and p21- Regulated BNIP3 Induction in Pancreatic Cancer Kanjoormana Aryan Manu1, Tin Fan Chai1, Jing Tsong Teh1, Wan Long Zhu1, Patrick J. Casey1,2, and Mei Wang1,3 Abstract Pancreatic cancer remains one of the most difficult to treat tion induced mitochondrial respiratory deficiency and cellular human cancers despite recent advances in targeted therapy. Inhi- energy depletion, leading to significant upregulation of p21. bition of isoprenylcysteine carboxylmethyltransferase (ICMT), an Furthermore, we characterized the role of p21 as a regulator and enzyme that posttranslationally modifies a group of proteins coordinator of cell signaling that responds to cell energy deple- including several small GTPases, suppresses proliferation of some tion. Apoptosis, but not autophagy, that is induced via p21- human cancer cells. However, the efficacy of ICMT inhibition on activated BNIP3 expression accounts for the efficacy of ICMT human pancreatic cancer has not been evaluated. In this study, we inhibition in sensitive pancreatic cancer cells in both in vitro and have evaluated a panel of human pancreatic cancer cell lines and in vivo models. In contrast, cells resistant to ICMT inhibition identified those that are sensitive to ICMT inhibition. In these demonstrated no mitochondria dysfunction or p21 signaling cells, ICMT suppression inhibited proliferation and induced changes under ICMT suppression. These findings not only identify apoptosis. This responsiveness to ICMT inhibition was confirmed pancreatic cancers as potential therapeutic targets for ICMT sup- in in vivo xenograft tumor mouse models using both a small- pression but also provide an avenue for identifying those subtypes molecule inhibitor and shRNA-targeting ICMT. Mechanistically, that would be most responsive to agents targeting this critical we found that, in sensitive pancreatic cancer cells, ICMT inhibi- enzyme. Mol Cancer Ther; 16(5); 1–10. Ó2017 AACR. Introduction sion of cell anabolism and proliferation in some cancers (10–12). However, the role of ICMT in human pancreatic cancer tumor- Pancreatic carcinomas are among the most difficult cancers to igenesis has not been directly addressed, despite confusing genetic treat, and the 5-year survival rate remains as low as 5% (1). studies in mice (6, 13, 14). Isoprenylcysteine carboxylmethyltransferase (ICMT) is the CDKN1A (often referred to as p21Cip1/Waf1 or p21) belongs to enzyme that catalyzes the last step of posttranslational prenyla- the Cip and Kip family of CDK inhibitors that bind to and inhibit tion-dependent modification of proteins. Most ICMT substrate the function of G cyclin/CDK complexes (15, 16). p21 has been proteins contain a C-terminal CAAX consensus motif. The car- 1 mostly studied as a factor that mediates the downstream signaling boxylmethylation by ICMT is essential for the proper function of of wild-type p53 as tumor suppressor, particularly in response to CAAX proteins by regulating their subcellular localization, pro- DNA damage, to cause cell-cycle arrest (17). However, a number tein–protein interactions, and/or protein stability (2–5). ICMT of studies have suggested that p21 performs tumor-suppressive has shown promise as a therapeutic target, as suggested by genetic functions independent of p53 (18–23). Apart from inhibiting and inhibitor studies (6–9). Recent investigations have indicated cell-cycle progression as a CDK inhibitor, p21 also regulates gene that inhibition of ICMT leads to metabolic disarray and suppres- transcription and apoptosis (18). Many cancers have altered or loss of p53 function, and p21 tumor suppressor functions are of particular interest in these cancers, among which many are of 1 Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, pancreatic origin (24). Singapore, Singapore. 2Department of Pharmacology and Cancer Biology, Duke Intrinsic or acquired resistance to apoptosis is a major reason University School of Medicine, Durham, North Carolina. 3Department of Bio- chemistry, National University of Singapore, Singapore, Singapore. for treatment failure of pancreatic cancers, and this has been frequently associated with the dysregulation of BCL2 family Note: Supplementary data for this article are available at Molecular Cancer – Therapeutics Online (http://mct.aacrjournals.org/). proteins (25 27). BNIP3 is a mitochondrial member of proa- poptotic BCL2 family protein containing a motif similar to the K.A. Manu and T.F. Chai contributed equally to this study. BH3 domain (26, 28–30). BNIP3 can interact with the prosurvival Corresponding Author: Mei Wang, Duke-NUS Medical School, 8 College Road, BCL2 family members BCL2 and BCLXL and thereby facilitates the Singapore 169857, Singapore. Phone: 65-6516-8608; E-mail: induction of apoptosis (31–33). In addition to its reported role in [email protected] apoptosis, BNIP3 has been identified as a regulator of autophagy doi: 10.1158/1535-7163.MCT-16-0703 (34, 35). Supporting its role in cancer survival, BNIP3 expression Ó2017 American Association for Cancer Research. was found to be downregulated in various types of cancers, www.aacrjournals.org OF1 Downloaded from mct.aacrjournals.org on September 28, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst February 6, 2017; DOI: 10.1158/1535-7163.MCT-16-0703 Manu et al. including in pancreatic adenocarcinoma (PDAC), in comparison sequences used are: p53-1, 50-GUAAUCUACUGGGACGGAATT- to normal tissues (36, 37). Loss of BNIP3 correlates with poorer 30 and p53-2, 50-GGUGAACCUUAGUACCUAATT-30; ATG5: 50- survival, and downregulation of BNIP3 results in increased resis- AUUCCAUGAGUUUCCGAUUGAUGGC-30. tance of pancreatic cancer to cytotoxic drug treatment (33, 38). Furthermore, BNIP3 expression was found to sensitize pancreatic Cloning and virus production cancer cells to apoptosis (39). BNIP3 shRNA was designed and cloned into pSuper retroviral In this study, we investigated the impact of ICMT inhibition on vector according to the User Manual (OligoEngine). The targeting human pancreatic cancer cells. We found that a subset of these sequences for BNIP3 were: (i) 50-CACGAGCGTCATGAAGAAA-30 cells are sensitive to ICMT inhibition through the inhibition of and (ii) 50-TACTGCTGGACGCACAGCA-30. MCherry-expressing mitochondria function and induction of an energy-depleted state, p21 shRNA retroviral vector with the target sequence 50- which results in the elevation of p21 and p21-dependent BNIP3 CTAGGCGGTTGAATGAGAG-30 was a gift from Dr. Mathijs Voor- expression, leading to cell-cycle arrest and apoptosis. hoeve. ICMT shRNA–expressing plasmids were constructed in lentiviral vector PLL3.7. The ICMT target sequences were: (i) 50- Materials and Methods CCCTGTCATTGTTCCACTATT-30 and (ii) 50-CTTGGTTTCGGCA- 0 Cells and ICMT inhibitor TCCTTCTT-3 . For expression, BCL-XL cDNA was cloned into ATCC pancreatic cancer cell lines MiaPaCa2, AsPC-1, PANC-1, retroviral vector pMSCV. HEK293T transfection and viral produc- BxPC-3, PANC-10.05, CAPAN-2, and HPAF-II were obtained tion were done according to the standard calcium phosphate from Duke University Tissue Culture Facility (Durham, NC) in protocol (42). 2011. These cell lines have been cultured per ATCC guidelines. The ICMT inhibitor cysmethynil was synthesized by the Duke Mouse xenograft studies Small Molecule Synthesis Facility via established methods (7, 40). MiaPaCa2 xenograft tumors were developed by subcutaneous Cysmethynil treatment of cells was performed as described in injection of 10 million MiaPaCa2 cells into the flanks of SCID prior publications from the laboratory (8, 10). mice that were 6 to 10 weeks old and weighed 18 to 20 g. Drug treatment, tumor measurement and euthanization were per- Cell culture, viability study, and soft-agar colony formed as described previously (8), in accordance with IACUC formation assay guidelines. Cells were seeded in standard DMEM containing 10% FBS and allowed to attach overnight. Cells were treated with various agents Statistical analysis and collected for protein and mRNA analysis at the time points GraphPad Prism (GraphPad) and Instat (GraphPad) software fi indicated in the respective gure legends. For glucose starvation were used for data analysis and presentation. To calculate the studies, culture media were replaced with glucose-free DMEM statistical significance, experimental groups were compared to the (GIBCO) supplemented with 10% FBS. Cell viability was deter- control group using Dunnet test one-way ANOVA to generate P mined using CellTiter 96 AQueous One Solution cell proliferation values. All experimental data are presented as mean Æ SD. assay (Promega) according to the manufacturer's instructions. Differences were considered statistically significant at P < 0.05. Soft-agar colony formation was determined as described (7). Results Flow cytometric analysis Saturating propidium iodide/DAPI staining was used for ana- Suppression of ICMT inhibits proliferation and induces lyzing cell cycle and apoptotic cell death as described (8). Flow apoptosis in human pancreatic cancer cells cytometry was done using Miltenyi Biotec MACSQuant VYB Flow Treatment of a panel of pancreatic cancer cell lines including instrument, and data were analyzed by FlowJo software (FlowJo). MiaPaCa2, AsPC-1, PANC-1, BxPC-3, CAPAN-2, PANC-10.05,
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