Abstract
The treatment of metastatic melanoma is challenging and in the vast majority of cases unsuccessful. Melanoma cells are resistant to most standard therapeutics. We have recently demonstrated that FKBP51 regulates melanoma response to ionizing radiation (IR). To find out molecular targets for radiosensitizing strategies to apply in this neoplasm, we investigated the changes of protein profiles in irradiated melanoma depleted or not of FKBP51, by protein microarray approach. Among the multiple molecules that were found modulated in our cell model, the decrease of several pPKC isoforms in the FKBP51-depleted (IR-sensitive) melanoma appeared to us particularly interesting, because PKC is involved in radiation response. Therefore, PKC was chosen for further investigation. After validating by western blot proteomics results, we found that targeting PKC, with the pan PKC inhibitor LY317615 or enzastaurin, significantly enhanced IR-induced cell death. Most interestingly, enzastaurin combined with IR appeared to be effective in eliminating a subset of melanoma cells expressing a stemness marker. Our study highlighted a role for proteomics in finding useful targets to overcome melanoma resistance, and suggested a combination treatment, which deserves to be investigated in a clinical setting.
Highlights
Melanoma was diagnosed in about 100.000 and killed 22.000 people in Europe in 2012 [1]
Melanoma cell depleted of FK506 binding protein 51 (FKBP51) is highly sensitive to ionizing radiation (IR) [5]
To confirm the effect of FKBP51 in regulation of PKC activation, we measured by western blot the levels of phosphoPKC, using a pan PKC phospho-antibody, in SAN and G361 melanoma cell lines, derived from metastatic and primary melanoma, respectively
Summary
Melanoma was diagnosed in about 100.000 and killed 22.000 people in Europe in 2012 [1]. Representing about the 3% of all diagnosed skin cancer, melanoma accounts for the 65% of deaths due to skin cancer [2]. Radiation therapy (RT) is a useful component of the therapeutic armamentarium for malignant melanoma, and may be indicated in about a fourth of patients bearing the disease [3]. The benefits from radiotherapy and cytotoxic drugs are limited because of the inherent resistance of melanoma. The definition of the molecular mechanisms underlying the phenomenon of cellular resistance to cytotoxic agents may be of help in the process of designing more effective treatments for melanoma
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call