Integrin αvβ3‐Akt signalling plays a role in radioresistance of melanoma

Abstract

Melanoma is a deadly type of skin cancer that is particularly difficult to treat owing to its resistance to radiation therapy. Here, we attempted to determine the key proteins responsible for melanoma radioresistance, with the aim of improving disease response to radiation therapy. Two melanoma cell lines, SK‐Mel5 and SK‐Mel28, with different radiosensitivities were analysed via RNA‐Seq (Quant‐Seq) and target proteins with higher abundance in the more radioresistant cell line, SK‐Mel28, identified. Among these proteins, integrin αvβ3, a well‐known molecule in cell adhesion, was selected for analysis. Treatment of SK‐Mel28 cells with cilengitide, an integrin αvβ3 inhibitor, as well as γ‐irradiation resulted in more significant cell death than γ‐irradiation alone. In addition, Akt, a downstream signal transducer of integrin αvβ3, showed high basic activation in SK‐Mel28 and was significantly decreased upon co‐treatment with cilengitide and γ‐irradiation. MK‐2206, an Akt inhibitor, exerted similar effects on the SK‐Mel28 cell line following γ‐irradiation. Our results collectively demonstrate that the integrin αvβ3‐Akt signalling pathway contributes to radioresistance in SK‐Mel28 cells, which may be manipulated to improve therapeutic options for melanoma.

Downregulation of ITGβ3 in colon adenocarcinoma reveals poor prognosis by affecting genome stability, cell cycle, and the tumor immune microenvironment

“…CLG can also promote the detachment of glioblastoma and mesothelioma cells from ECM components through exposed RGD sequences, resulting in anoikis-dependent apoptosis and inhibition of invasion (32). Notably, as an avb3 integrin-specific inhibitor, CLG also shows encouraging outcomes in pancreatic cells, gliomas, and some metastatic solid tumors, according to some clinical trials (33)(34)(35). However, a further large clinical study indicated that adding CLG to temozolomide chemoradiotherapy does not improve outcomes (36).…”

Recent advances in radiosensitivity determinants in melanoma

“…Microarray analysis of two melanoma cell lines, SK-Mel5 and SK-Mel28, with different radiosensitivities, was employed to identify target proteins enriched in the more radioresistant cell line, SK-Mel28, among which integrin avb3 adhesion molecule as well as Akt, were found to contribute to radioresistance, supporting the therapeutic potential of targeting these molecules [79].…”

The Cellular Origins of Cancer-Associated Fibroblasts and Their Opposing Contributions to Pancreatic Cancer Growth

“…Premature senescence seems to be also induced in normal human fibroblasts as a result of chronic low dose rate (LDR) exposure (5 or 15 mGy/h) of gamma rays ( Fujimori et al, 2005 ). In addition to inducing premature cellular senescence, exposing CAFs to RT results in the potent induction of multiple DNA damage response (DDR) foci as well as the inhibition of the proliferative, migrative, and invasive capacity of these fibroblasts ( Goel et al, 2013 ; Li et al, 2018 ; Im et al, 2020 ). Senescent CAFs have been described to present a senescence-associated secretory phenotype that is characterized by the upregulation and secretion of various substances (e.g., CXCL12, TGF-β1, IGF-1, IGFBP2, and NO) ( Li et al, 2016 ; Ansems and Span, 2020 ), some of which are pro-tumorigenic factors, such as IL-6, IL-8, and osteopontin, and are linked to stroma-mediated therapeutic resistance ( Krisnawan et al, 2020 ).…”