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

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.

• Authors: Iwona Karwaciak, Anna Sałkowska, Kaja Karaś, Jarosław Dastych, Marcin Ratajewski
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 9 (May 10 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34068624 (Publication Type: Journal Article)

Chemical References

• H2AX protein, human
• Histones
• EGFR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins c-akt
• raf Kinases
• SIRT2 protein, human
• Sirtuin 2
• Cisplatin

Topics

• Cell Line, Tumor
• Cisplatin (adverse effects, pharmacology)
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Histones (genetics)
• Humans
• MAP Kinase Signaling System (drug effects)
• Melanoma (drug therapy, genetics, pathology)
• Proto-Oncogene Proteins c-akt
• Sirtuin 2 (antagonists & inhibitors, genetics)
• raf Kinases (genetics)