MT2A Promotes Oxaliplatin Resistance in Colorectal Cancer Cells
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ORIGINAL PAPER
MT2A Promotes Oxaliplatin Resistance in Colorectal Cancer Cells Zhicheng Zhao1 Guojing Zhang1 Weidong Li ●
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Received: 16 January 2020 / Accepted: 24 June 2020 / Published online: 7 July 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract We aimed to understand the molecular mechanism underlying the incidence of Oxaliplatin resistance in colorectal cancer. The Oxaliplatin-resistant (OR) HT29 colorectal cell line was established by long-term exposure to Oxaliplatin. Cell viability and proliferation were determined by the 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide and direct counting assays, respectively. Transcript level of metallothionein 2A (MT2A) was measured by real-time polymerase chain reaction. Protein levels of MT2A, BRCA1-associated RING domain 1 (BARD1), BRCA1, and β-actin were quantified by immunoblotting. Direct interaction between MT2A with BARD1 and BRCA1 was analyzed by co-immunoprecipitation. Colocalization between of MT2A and BARD1 was determined by immunofluorescence. MT2A was upregulated in OR cells at both transcript and protein levels. Knockdown of MT2A in HT29 OR cells improved sensitivity to Oxaliplatin, while ectopic overexpression of MT2A conferred HT29 cells relative resistance to Oxaliplatin. We further demonstrated that MT2A interacted with and positively regulated BARD1/BRCA1 in colorectal cancer cells. BARD1 overexpression partially restored the compromised Oxaliplatin resistance elicited by MT2A deficiency in terms of both cell proliferation and viability. Our data highlighted the critical contributions of MT2A-BARD1/BRCA1 in Oxaliplatin resistance in colorectal cancer cells. Keywords Oxaliplatin resistance Colorectal cancer MT2A BARD1 ●
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Introduction Colorectal cancer is a human malignancy derived from the colon or rectum [1]. Worldwide, colorectal cancer is the third most common form of cancer, and according to the Cancer Statistics 2019, there were 1.09 million new cases diagnosed and 551,000 deaths claimed by this disease [2]. Colorectal cancer is often diagnosed clinically by biopsy during the sigmoidoscopy or colonoscopy, and followed by medical imaging to evaluate the possibility and extent of metastasis [3]. Screening with preventive purpose is recommended for the elders above 50-year old [4]. Recognized risk factors associated with this disease include old age and lifestyle factors, and only a small portion of
Supplementary information The online version of this article (https:// doi.org/10.1007/s12013-020-00930-5) contains supplementary material, which is available to authorized users. * Weidong Li [email protected] 1
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
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cases are due to genetic disorders [5]. Diet, obesity, and smoking are all documented to be linked to the incidence of colorectal cancer. Currently, the treatment options for colorectal cancer patients include some combination of surgery, radiation therap
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