Kiss1 in Regulation of Metastasis and Response to Antitumor Drugs T ⁎ Cristina Corno, Paola Perego
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Drug Resistance Updates 42 (2019) 12–21 Contents lists available at ScienceDirect Drug Resistance Updates journal homepage: www.elsevier.com/locate/drup KiSS1 in regulation of metastasis and response to antitumor drugs T ⁎ Cristina Corno, Paola Perego Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42/via Venezian 1, 20133 Milan, Italy ARTICLE INFO ABSTRACT Keywords: Metastatic dissemination of tumor cells represents a major obstacle towards cancer cure. Tumor cells with KiSS1 metastatic capacity are often resistant to chemotherapy. Experimental efforts revealed that the metastatic cas- GPR54 cade is a complex process that involves multiple positive and negative regulators. In this respect, several me- Cancer tastasis suppressor genes have been described. Here, we review the role of the metastasis suppressor KiSS1 in Metastasis regulation of metastasis and in response to antitumor agents. Physiologically, KiSS1 plays a key role in the Drug response activation of the hypothalamic-pituitary-gonadal axis regulating puberty and reproductive functions. KiSS1- derived peptides i.e., kisspeptins, signal through the G-protein coupled receptor GPR54. In cancer, KiSS1 sig- naling suppresses metastases and maintains dormancy of disseminated malignant cells, by interfering with cell migratory and invasive abilities. Besides, KiSS1 modulates glucose and lipid metabolism, by reprogramming energy production towards oxidative phosphorylation and β-oxidation. Loss or reduced expression of KiSS1, in part through promoter hypermethylation, is related to the development of metastases in various cancer types, with some conflicting reports. The poorly understood role of KiSS1 in response to chemotherapeutic agents appears to be linked to stimulation of the intrinsic apoptotic pathway and inhibition of cell defense factors (e.g., glutathione S-transferase-π) as well as autophagy modulation. Deciphering the molecular basis underlying regulation of the metastatic potential is crucial for the establishment of novel treatment strategies. 1. Introduction invasion by tumor cells followed by intravasation in blood or lymphatic vessels, arrest in distant organs, extravasation and metastatic coloni- Although there has been a revolution in cancer care and treatment zation (Turajlic and Swanton, 2016). Cells may engage dormancy driven by the discovery of a multitude of alterations in tumor cells, by programs that impair cell proliferative ability as well as pro-angiogenic the advent of new technologies and by efforts directed at early detec- features (Lambert et al., 2017). Metastatic spread involves several po- tion and prevention of cancer, it has failed to lead to a durable control sitive and negative regulators, the latter including metastasis sup- of neoplastic diseases, particularly when metastases develop. Thus, pressor genes often lost in tumors due to reduced transcription. Several metastatic dissemination of tumor cells represents a major limitation to metastasis suppressors have been described (Shoushtari et al., 2011; the cure for different types of cancer (Popper, 2016; Fakih, 2015; Smith and Theodorescu, 2009) and among them KiSS1 appears to act at Middleton et al., 2018). Frequently, disease outcome remains un- the interface of metastasis and drug response. In fact, KiSS1 has been satisfactory due to drug resistance and metastatic dissemination. Drug implicated in suppressing the metastatic phenotype of cancer cells as resistance of tumor cells is often associated to an increase in the me- well as in sensitizing them to conventional chemotherapy (Beck and tastatic ability (Naiditch et al., 2015; Corno et al., 2017), with the ac- Welch, 2010; Jiffar et al., 2011). quisition of mesenchymal features and the occurrence of the so-called Metastatic spread involves different target organs. Lymph nodes are epithelial to mesenchymal transition (EMT), a plastic program sup- the most frequently affected organs, whereas liver, lung, brain and bone pressing epithelial markers while inducing mesenchymal markers represent preferential distant target organs. Liver metastases, more (Chaffer et al., 2016). frequent than primary hepatic tumors and often symptomless, derive Metastatic spread is a complex phenomenon consisting of the de- from multiple tumor types such as breast, gastrointestinal cancer and tachment of tumor cells from the primary tumor towards close or dis- melanoma (Clark et al., 2016). Lung metastases are generated from tant sites where tumor cells grow and generate new masses (Lambert various extra-thoracic tumors such as breast, colon and skin cancer et al., 2017). The process occurs in multiple steps starting with local (Altorki et al., 2018). Brain metastases are the most common type of ⁎ Corresponding author. E-mail address: [email protected] (P. Perego). https://doi.org/10.1016/j.drup.2019.02.001 Received 28 December 2018; Received in revised form 3 February 2019; Accepted 6 February 2019 1368-7646/ © 2019 Elsevier Ltd. All rights reserved. C. Corno and P. Perego Drug Resistance Updates 42 (2019) 12–21 central nervous system (CNS) tumors being more frequent compared to KiSS1R expression in the metastasis suppressive effect of KiSS1 has primary brain tumors (Valiente et al., 2018); the most common origi- been reported in several studies in different tumor types such as renal nate from lung cancer, breast cancer and malignant melanoma cell carcinoma, pancreatic cancer and colon cancer (Shoji et al., 2009; (Gavrilovic and Posner, 2005). Skeletal metastases derive mainly from Uno et al., 2016; Kim et al., 2018). breast, lung, prostate and renal cancer (Weidle et al., 2016). Overall, less attention has been paid to metastasis suppressors than to factors 3. KiSS1 signaling in physiology and cancer promoting metastasis, likely given to the propensity to hit mechanisms favoring tumor aggressiveness more than to restore mechanisms sup- Canonical signaling of KiSS1 occurs trough the GPR54 receptor pressing the aggressive behavior of tumor cells. However, from the (Wahab et al., 2016). The ligand of this G-protein coupled receptor is nineties, many studies have implicated KiSS1 in metastasis suppression peculiar because it is not a single protein, but consists of multiple in different tumor types, and the knowledge on its role in tumor biology peptides (Kotani et al., 2001). In fact, the KISS1 gene encodes for a 145- has been markedly deepened. aa hydrophobic polypeptide, from which the 54-amino acid protein Here, we review the role of KiSS1 in regulating metastatic spread, kisspeptin-54 (KP54, also known as metastin) is cleaved (Kotani et al., taking into account its signaling pathway, the recently reported func- 2001; Harihar et al., 2014). The KiSS1 protein which harbors an N- tion in regulation of metabolism as well as conflicting biological func- terminal secretion signal peptide and KiSS1 processed by furin or pos- tions emerging from the literature about its control of the metastatic sibly by additional members of the pro-protein convertase family of cell ability. In addition, we examine the poorly understood aspects in- proteases, has been proposed to occur outside the cell (Harihar et al., volving KiSS1 in the regulation of sensitivity of tumor cells to che- 2014; Nash et al., 2007; Beck and Welch, 2010). Peptides derived from motherapeutic drugs. Finally, we discuss the therapeutic potential of the KiSS1 polypeptide even shorter than KP54, are collectively named KiSS1-derived peptides (i.e., kisspeptins) and how advances in the field kisspeptins (consisting of 10, 13 and 14 amino acids) and share a of KiSS1 biology may be exploited in the search for new therapies or common RF-amidate motif (Arg-Phe-NH2) with metastin (Ohtaki et al., biomarkers of response. 2001). In the full-length protein, the amino acid sequence of KP54 contains pairs of basic residues with the R66-R and GK123-R acting as 2. Overview on KiSS1 cleavage sites for furin or other convertases. The proteolytic processing of KiSS1, occurring with modes similar to that of neuropeptides (Yang The KISS1 gene is a metastasis suppressor originally identified in et al., 2016), was already predicted upon identification of the kis- melanoma cells, in which metastatic spread had been suppressed by speptins-GPR54 interaction due to the presence of basic residues in the introduction of human chromosome 6 (Lee et al., 1996). full amino acid protein sequence leading to KP54; the shorter peptides This chromosome transfer approach led to a misleading assignment were probably the result of metastin instability leading to KP10, KP13 of the KISS1 gene to chromosome 6; in fact, further studies clarified that and KP14 (Kotani et al., 2001). In a recent study, an exclusive role for the KISS1 gene mapped to the long arm of chromosome 1 (1q32-q41) as furin in KiSS1 processing has been demonstrated based on the fact that shown by fluorescence in situ hybridization (West et al., 1998) and its upon treatment of KiSS1 overexpressing cells with pro-protein con- expression was likely regulated by a gene localized on chromosome 6 vertase inhibitors and based on the evidence that knockdown of furin (Miele et al., 2000). Functional approaches indicated that KISS1 was but not of other proteases (i.e., PCSK5 or PCSK7), abolished KiSS1 indeed a metastasis suppressor in melanoma cells and incorrectly in processing (Harihar et al., 2014). breast cancer due to a cell line misidentification (Lee et al., 1996, Lee