Targeting SIRT2 Sensitizes Melanoma Cells to Cisplatin via an EGFR-Dependent Mechanism.

Iwona Karwaciak,Jarosław Dastych,Kaja Karaś,Marcin Ratajewski,Anna Sałkowska

doi:10.3390/ijms22095034

Iwona Karwaciak, Jarosław Dastych + Show 3 more

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https://doi.org/10.3390/ijms22095034

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Abstract

Melanoma cells are resistant to most anticancer chemotherapeutics. Despite poor response rates and short-term efficacy, chemotherapy remains the main approach to treating this cancer. The underlying mechanisms of the intrinsic chemoresistance of melanoma remain unclear, but elucidating these mechanisms is important to improve the efficacy of chemotherapy regimens. Increasing evidence suggests that sirtuin 2 (SIRT2) plays a key role in the response of melanoma cells to chemotherapeutics; thus, in the present study, we evaluated the impact of shRNA-mediated and pharmacological inhibition of SIRT2 on the sensitivity of melanoma cells to cisplatin, which is used in several regimens to treat melanoma patients. We found that cells with SIRT2 inhibition revealed increased sensitivity to cisplatin and exhibited increased accumulation of γ-H2AX and reduced EGFR-AKT-RAF-ERK1/2 (epidermal growth factor receptor-protein B kinase–RAF kinase-extracellular signal-regulated kinase 1/2) pathway signaling compared to control cells. Thus, our results show that sirtuin 2 inhibition increased the in vitro efficacy of cisplatin against melanoma cells.

Highlights

IntroductionMasutaka FurueWhile melanoma is a relatively rare skin neoplasm, it is the most dangerous skin neoplasm, accounting for the majority of deaths caused by this tumor type [1]
Masutaka FurueWhile melanoma is a relatively rare skin neoplasm, it is the most dangerous skin neoplasm, accounting for the majority of deaths caused by this tumor type [1]
The mechanistic effect of sirtuin 2 inhibition on melanoma cell resistance may involve the epidermal growth factor receptor (EGFR), which we previously found to be directly regulated by SIRT2 in melanoma cells [9], and a decrease in AKT-RAF-ERK1/2 signaling phosphorylation

Summary

Introduction

Masutaka FurueWhile melanoma is a relatively rare skin neoplasm, it is the most dangerous skin neoplasm, accounting for the majority of deaths caused by this tumor type [1]. The high drug resistance of melanomas may be related to metabolic processes involved in melanin production by the melanocytes, from which melanoma originates. It should be noted that numerous other unknown mechanisms are involved in multidrug resistance of melanoma cells (intrinsic and acquired) that subsequently lead to poor response rates and low efficacy of chemotherapeutic treatment. This resistance is considered to be the main cause of the failure of standard or targeted therapies against melanoma and other cancers [5]. It is important to elucidate the processes responsible for resistance to a specific drug, as this may provide potential therapeutic targets and improve the efficacy of known therapies

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