Kisspeptin-mediated improvement of sensitivity to BRAF inhibitors in vemurafenib-resistant melanoma cells

Abstract

Metastatic dissemination is still one of the major causes of death of melanoma’s patients. KiSS1 is a metastasis suppressor originally identified in melanoma cells, known to play an important physiological role in mammals’ development and puberty. It has been previously shown that expression of KiSS1 could be increased in lung cancer cells using epigenetic agents, and that KiSS1 could have a pro-apoptotic action in combination with cisplatin. Thus, the aim of the present study was to examine in human melanoma vemurafenib sensitive- and -resistant BRAF mutant cells characterized by different mutational profiles and KiSS1, KiSS1 receptor and KiSS1 drug-induced release, if peptides derived from KiSS1 cleavage, i.e., kisspeptin 54, could increase the sensitivity to vemurafenib of human melanoma, using cellular, molecular and biochemical approaches. We found that kisspeptin 54 increases vemurafenib pro-apoptotic activity in a statistically significant manner, also in drug resistant cellular models. The efficacy of the combination appears to reflect the intrinsic susceptibility of each cell line to PLX4032-induced apoptosis, together with the different mutational profile as well as perturbation of proteins regulating the apoptotic pathway, The results presented here highlight the possibility to exploit KiSS1 to modulate the apoptotic response to therapeutically relevant agents, suggesting a multitasking function of this metastasis suppressor.

KiSS-1 Modulation by Epigenetic Agents Improves the Cisplatin Sensitivity of Lung Cancer Cells

“…This study was conceived to examine if combined treatment with epigenetic agents, i.e., HDAC or DNMT inhibitors, could improve the anti-proliferative effect of cisplatin and whether the antitumor efficacy of the combination could be related to the metastasis suppressor KiSS-1, that has been recently implicated by us and others in drug-sensitizing effects [38][39][40]. For this purpose, both cisplatin-sensitive H460 and -resistant H460/Pt cells were employed.…”

“…Since KiSS-1 has been reported to favor apoptosis in specific cellular contexts [38,40], we carried out an analysis of KiSS-1 release in the culture medium treatment with the different drugs and drug combinations. Because KiSS-1 encodes an unstable polypeptide that is promptly cleaved into kisspeptins, we used ELISA to quantitatively measure the effect of treatment on KiSS-1-derived peptides.…”

“…The obtained results suggested a possible chemo-sensitizing role of KiSS-1 to cisplatin. Indeed, KiSS-1 mRNA levels have been shown to be up-regulated by HDAC and DNMT inhibitors [21,42], and KiSS-1 has been proposed to sensitize head and neck squamous cell carcinoma, lung cancer models to cisplatin, and melanoma cells to vemurafenib [38][39][40]. Sensitization appers to be related to enhanced apoptotic response; both AZA and SAHA have been shown to upmodulate KiSS-1 expression [21,39], suggesting that KiSS-1 upmodulation favors apoptosis induction.…”

“…The MAPKs acting downstream of GPR54 in tumor cells play both protective and pro-apoptotic roles depending on the molecular context [37]. More recently, KiSS-1 has been reported to play a role in modulating the apoptotic response of melanoma cells to antitumor drug exposure, including vemurafenib [38]. This feature allows for the speculation that the combination of antitumor therapeutics with KPs may improve patients' response to multiple therapeutic agents [38].…”