TXNL1-XRCC1 pathway regulates cisplatin-induced cell death and contributes to resistance in human gastric cancer

W Xu,M Wang,J Zhou,J Zhang,O D Røe,X Wu,R Zhang,F Qiang,S Xu,P Ni,Y Zhang,S Wang,A Li,Q Chen

doi:10.1038/cddis.2014.27

Abstract

Cisplatin is a cytotoxic platinum compound that triggers DNA crosslinking induced cell death, and is one of the reference drugs used in the treatment of several types of human cancers including gastric cancer. However, intrinsic or acquired drug resistance to cisplatin is very common, and leading to treatment failure. We have recently shown that reduced expression of base excision repair protein XRCC1 (X-ray repair cross complementing group1) in gastric cancerous tissues correlates with a significant survival benefit from adjuvant first-line platinum-based chemotherapy. In this study, we demonstrated the role of XRCC1 in repair of cisplatin-induced DNA lesions and acquired cisplatin resistance in gastric cancer by using cisplatin-sensitive gastric cancer cell lines BGC823 and the cisplatin-resistant gastric cancer cell lines BGC823/cis-diamminedichloridoplatinum(II) (DDP). Our results indicated that the protein expression of XRCC1 was significantly increased in cisplatin-resistant cells and independently contributed to cisplatin resistance. Irinotecan, another chemotherapeutic agent to induce DNA damaging used to treat patients with advanced gastric cancer that progressed on cisplatin, was found to inhibit the expression of XRCC1 effectively, and leading to an increase in the sensitivity of resistant cells to cisplatin. Our proteomic studies further identified a cofactor of 26S proteasome, the thioredoxin-like protein 1 (TXNL1) that downregulated XRCC1 in BGC823/DDP cells via the ubiquitin-proteasome pathway. In conclusion, the TXNL1-XRCC1 is a novel regulatory pathway that has an independent role in cisplatin resistance, indicating a putative drug target for reversing cisplatin resistance in gastric cancer.

Highlights

20%, it becomes a major cause of both morbidity and mortality,[1,2] where even resectable disease has a 50–90% risk of recurrence and death.[3]
We addressed the question whether the downregulated thioredoxin-like protein 1 (TXNL1) expression in BGC823/DDP cells contributes to the degradation of XRCC1 linked to cisplatin resistance? We investigated the role of TXNL1 as an antioxidant molecule in response to oxidative stress in BGC823 cells and BGC823/DDP cells by treatment with another chemotherapy agent arsenic trioxide (As2O3), which is known to induce DNA damage and apoptosis via reactive oxygen species (ROS) production in cancer cells
We have provided new evidences supporting that cisplatin resistance developed in the gastric cancer cells is at least in part because of the XRCC1 overexpression as a result of inhibition of TXNL1, presumably leading to a super strong capacity of DNA repair

Summary

Introduction

20%, it becomes a major cause of both morbidity and mortality,[1,2] where even resectable disease has a 50–90% risk of recurrence and death.[3]. One of the most widely used and effective anticancer agents, targets the DNA by inducing DNA adducts and crosslinks, leading to single- and double-strand breaks (DSBs), activating the DNA damage response, resulting in apoptotic cell death.[6] Cisplatin is the treatment backbone in a variety of cancers including gastric cancer,[7,8,9,10,11] but intrinsic and acquired resistance impairs its effectiveness to a high degree This phenomenon is even common in the adjuvant setting where no macroscopic tumor is evident. Several studies have suggested an association between XRCC1 and cisplatin resistance,[17,18] the contribution of XRCC1 to cisplatin resistance in gastric cancer and underlying mechanisms are not fully understood

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