Metformin overcomes resistance to cisplatin in triple-negative breast cancer (TNBC) cells by targeting RAD51

Autor: Jeong Ah Han, Su Jin Kim, Ji Hae Kim, Eun Jung Lee, Min Ju Kang, Serk In Park, Sun Hwa Park, Jung Ok Lee, Ji Wook Moon, Il Hyeok Seo, Won Seok Byun, Hyeon Soo Kim, Shin Ae Kim
Rok vydání: 2019
Předmět:
Combination therapy
Cell Survival
medicine.medical_treatment
Antineoplastic Agents
Triple Negative Breast Neoplasms
lcsh:RC254-282
03 medical and health sciences
0302 clinical medicine
Breast cancer
Cell Movement
In vivo
Cell Line
Tumor
Antineoplastic Combined Chemotherapy Protocols
medicine
Animals
Humans
Viability assay
Cisplatin resistance
Triple-negative breast cancer
030304 developmental biology
Cisplatin
Mice
Inbred BALB C
0303 health sciences
Chemotherapy
business.industry
Mammary Neoplasms
Experimental
Drug Synergism
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.disease
Metformin
Gene Expression Regulation
Neoplastic
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Cancer research
RAD51
Female
Rad51 Recombinase
business
TNBC
Research Article
medicine.drug
Zdroj: Breast Cancer Research, Vol 21, Iss 1, Pp 1-18 (2019)
Breast Cancer Research : BCR
ISSN: 1465-542X
DOI: 10.1186/s13058-019-1204-2
Popis: Background Chemotherapy is a standard therapeutic regimen to treat triple-negative breast cancer (TNBC); however, chemotherapy alone does not result in significant improvement and often leads to drug resistance in patients. In contrast, combination therapy has proven to be an effective strategy for TNBC treatment. Whether metformin enhances the anticancer effects of cisplatin and prevents cisplatin resistance in TNBC cells has not been reported. Methods Cell viability, wounding healing, and invasion assays were performed on Hs 578T and MDA-MB-231 human TNBC cell lines to demonstrate the anticancer effects of combined cisplatin and metformin treatment compared to treatment with cisplatin alone. Western blotting and immunofluorescence were used to determine the expression of RAD51 and gamma-H2AX. In an in vivo 4T1 murine breast cancer model, a synergistic anticancer effect of metformin and cisplatin was observed. Results Cisplatin combined with metformin decreased cell viability and metastatic effect more than cisplatin alone. Metformin suppressed cisplatin-mediated RAD51 upregulation by decreasing RAD51 protein stability and increasing its ubiquitination. In contrast, cisplatin increased RAD51 expression in an ERK-dependent manner. In addition, metformin also increased cisplatin-induced phosphorylation of γ-H2AX. Overexpression of RAD51 blocked the metformin-induced inhibition of cell migration and invasion, while RAD51 knockdown enhanced cisplatin activity. Moreover, the combination of metformin and cisplatin exhibited a synergistic anticancer effect in an orthotopic murine model of 4T1 breast cancer in vivo. Conclusions Metformin enhances anticancer effect of cisplatin by downregulating RAD51 expression, which represents a novel therapeutic target in TNBC management.
Databáze: OpenAIRE
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