Targeting REV7 effectively reverses 5-FU and oxaliplatin resistance in colorectal cancer
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Cancer Cell International Open Access
PRIMARY RESEARCH
Targeting REV7 effectively reverses 5‑FU and oxaliplatin resistance in colorectal cancer Xianjun Sun1, Wenhou Hou2, Xin Liu1, Jie Chai1, Hongliang Guo1 and Jinming Yu2*
Abstract Background: Despite an enormous research effort, patients diagnosed with advanced colorectal cancer (CRC) still have low prognosis after surgical resection and chemotherapy. The major obstacle for CRC treatment is chemoresistance to front line anti-cancer drugs, such as 5-fluorouracil (5-FU) and oxaliplatin. However, the mechanism of chemoresistance to these drugs remains unclear. Methods: Cell viability to 5-FU and oxaliplatin was measured by the CellTiter-Glo® 2.0 Cell Viability Assay. The endogenous REV7 protein in CRC cells was detected by western blotting. The translesion synthesis (TLS) events were measured by plasmid-based TLS efficiency assay. Cell apoptosis was evaluated by caspase3/7 activity assay. The in vivo tumor progression was analyzed by HT29 xenograft mice model. Results: In this study, we found that expression of REV7, which is a key component of translesion synthesis (TLS) polymerase ζ (POL ζ), is significantly increased in both 5-FU and oxaliplatin resistant CRC cells. TLS efficiency analysis revealed that upregulated REV7 protein level results in enhanced TLS in response to 5-FU and oxaliplatin. Importantly, inhibition of REV7 by CRISPR/Cas9 knockout exhibited significant synergy with 5-FU and oxaliplatin in cell culture and murine xenograft model. Conclusion: These results suggest that combination of REV7 deficiency and 5-FU or oxaliplatin has strong inhibitory effects on CRC cells and identified REV7 as a promising target for chemoresistant CRC treatment. Keywords: REV7, TLS, 5-FU, Oxaliplatin, Resistance, Colorectal cancer Background Colorectal cancer (CRC) is the third most common cancers worldwide and is often diagnosed at advanced stages [1]. The 5-year survival rate for patients with advanced stage CRC is only 10–15% largely due to resistance to chemotherapy and lack of alternative regimens [2]. Therefore, understanding of mechanisms underlying chemoresistance is extremely important for improving chemotherapy in CRC. 5-fluorouracil (5-FU) has been used as the mainstay of chemotherapy for CRC patients *Correspondence: [email protected] 2 Department of Radiotherapy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academic Sciences, 440 Jiyan Rd., Jinan 250117, Shandong, China Full list of author information is available at the end of the article
since the 1950s [3]. Other chemotherapy drugs, such as oxaliplatin and irinotecan, have been developed and approved for advanced CRC treatment [4]. 5-FU is a synthetic nucleotide analog that inhibits thymidylate synthase and incorporates its metabolites into DNA, hereby leading to cell death [5]. Oxaliplatin is the third generation-platinum drug that causes cytotoxicity through introducing platinum–DNA adducts [6]. Both 5-FU and oxaliplatin treatments result in di
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