Characterization of the role of TMEM45A in cancer cell sensitivity to cisplatin

• Published in: Cell death & disease Vol. 10; no. 12; pp. 919 - 18
• Main Authors: Schmit, Kathleen, Chen, Jia-Wei, Ayama-Canden, Sophie, Fransolet, Maude, Finet, Laure, Demazy, Catherine, D’Hondt, Lionel, Graux, Carlos, Michiels, Carine
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.12.2019; Springer Nature B.V
• Subjects: 13/1; 13/2; 13/31; 13/95; 14; 14/63; 38/39; 38/77; 38/91; 42/89; 631/67/1059; 631/67/1536; 631/67/1857; 631/80/82/23; Adult; Aged; Aged, 80 and over; Antibodies; Apoptosis; Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Breast cancer; Cancer; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Cell Biology; Cell Culture; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Chemotherapy; Cisplatin; Cisplatin - administration & dosage; Cisplatin - adverse effects; DNA damage; DNA repair; DNA Repair - drug effects; Drug Resistance, Neoplasm - genetics; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Head & neck cancer; Humans; Hypoxia; Immunology; Kidney cancer; Kinases; Life Sciences; Male; Membrane Proteins - genetics; Middle Aged; Proteins; Renal cell carcinoma; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - drug therapy; Squamous Cell Carcinoma of Head and Neck - genetics; Squamous Cell Carcinoma of Head and Neck - pathology
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-2088-x

TMEM45A is a transmembrane protein involved in tumor progression and cancer resistance to chemotherapeutic agents in hypoxic condition. It is correlated to a low breast cancer patient overall survival. However, little is known about this protein, in particular the mechanisms by which TMEM45A modulates cancer cell chemosensitivity. In this work, the messenger RNA expression of TMEM45A was assessed in head and neck squamous cell carcinoma (HNSCC) and renal cell carcinoma (RCC) biopsies. TMEM45A was upregulated in patients diagnosed for head and neck or renal cancer. Then, the implication of this protein in cisplatin sensitivity was explored in SQD9 and RCC4 + pVHL cells. TMEM45A inactivation decreased cell proliferation and modulated cell responses to cisplatin. Indeed, TMEM45A inactivation increased the sensitivity of SQD9 cells to cisplatin, whereas it rendered RCC4 + pVHL cells resistant to this anticancer agent. Through RNA-sequencing analysis, we identified several deregulated pathways that indicated that the impact on cisplatin sensitivity may be associated to the inhibition of DNA damage repair and to UPR pathway activation. This study demonstrated, for the first time, an anti or a pro-apoptotic role of this protein depending on the cancer type and highlighted the role of TMEM45A in modulating patient responses to treatment.