The Fanconi anemia pathway sensitizes to DNA alkylating agents by inducing JNK-p53-dependent mitochondrial apoptosis in breast cancer cells Retraction in /10.3892/ijo.2022.5343

Zhao,Lin; Li,Yanlin; He,Miao; Song,Zhiguo; Lin,Shu; Yu,Zhaojin; Bai,Xuefeng; Wang,Enhua; Wei,Minjie

doi:10.3892/ijo.2014.2400

The Fanconi anemia pathway sensitizes to DNA alkylating agents by inducing JNK-p53-dependent mitochondrial apoptosis in breast cancer cells

Retraction in 10.3892/ijo.2022.5343

Authors:
- Lin Zhao
- Yanlin Li
- Miao He
- Zhiguo Song
- Shu Lin
- Zhaojin Yu
- Xuefeng Bai
- Enhua Wang
- Minjie Wei
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Affiliations: Department of Pharmacology, School of Pharmaceutical Science, China Medical University, Heping Ward, Shenyang, Liaoning 110001, P.R. China, Institute of Pathology and Pathophysiology, China Medical University, Heping Ward, Shenyang, Liaoning 110001, P.R. China
Published online on: April 28, 2014 https://doi.org/10.3892/ijo.2014.2400
Pages: 129-138

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Abstract

The Fanconi anemia/BRCA (FA/BRCA) DNA damage repair pathway plays a pivotal role in the cellular response to DNA alkylating agents and greatly influences drug response in cancer treatment. However, the molecular mechanisms underlying the FA/BRCA pathway reversed resistance have received limited attention. In the present study, we investigated the effect of Fanconi anemia complementation group F protein (FANCF), a critical factor of the FA/BRCA pathway, on cancer cell apoptosis induced by DNA alkylating agents such as mitomycin c (MMC). We found that FANCF shRNA potentiated MMC-induced cytotoxicity and apoptosis in MCF-7 and MDA-MB-231 breast cancer cells. At a mechanistic level, FANCF shRNA downregulated the anti-apoptotic protein Bcl-2 and upregulated the pro-apoptotic protein Bax, accompanied by release of cyt-c and smac into the cytosol in MMC-treated cells. Furthermore, activation of caspase-3 and -9, other than caspase-8, cleavage of poly(ADP ribose) polymerase (PARP), and a decrease of mitochondrial membrane potential (MMP) indicated that involvement of the mitochondrial apoptotic pathway in FANCF silencing of MMC-treated breast cancer cells. A decrease in IAP family proteins XIAP and survivin were also observed following FANCF silencing in MMC-treated breast cancer cells. Notably, FANCF shRNA was able to increase p53 levels through activation of the JNK pathway in MMC-treated breast cancer cells. Furthermore, p53 inhibition using pifithrin-α abolished the induction of caspase-3 and PARP by FANCF shRNA and MMC, indicating that MMC-induced apoptosis is substantially enhanced by FANCF shRNA via p53-dependent mechanisms. To our knowledge, we provide new evidence for the potential application of FANCF as a chemosensitizer in breast cancer therapy.

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