N-myc downstream-regulated gene 1 promotes oxaliplatin-triggered apoptosis in colorectal cancer cells via enhancing the ubiquitination of Bcl-2.

Xiao Yang,Luyang Zhang,Jiaoyang Lu,Chaoran Yu,Jing Sun,Yanfeng Lv,Fan Zhu,Minhua Zheng

doi:10.18632/oncotarget.17711

Xiao Yang, Luyang Zhang + Show 6 more

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https://doi.org/10.18632/oncotarget.17711

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Abstract

N-myc downstream-regulated gene1 (NDRG1) has been identified as a potent tumor suppressor gene. The molecular mechanisms of anti-tumor activity of NDRG1 involve its suppressive effects on a variety of tumorigenic signaling pathways. The purpose of this study was to investigate the role of NDRG1 in the apoptosis of colorectal cancer (CRC) cells. We first collected the clinical data of locally advanced rectal cancer (LARC) patients receiving oxaliplatin-based neoadjuvant chemotherapy in our medical center. Correlation analysis revealed that NDRG1 positively associated with the downstaging rates and prognosis of patients. Then, the effects of over-expression and depletion of NDRG1 gene on apoptosis of colorectal cancer were tested in vitro and in vivo. NDRG1 over-expression promoted apoptosis in colorectal cancer cells whereas depletion of NDRG1 resulted in resistance to oxaliplatin treatment. Furthermore, we observed that Bcl-2, a major anti-apoptotic protein, was regulated by NDRG1 at post-transcriptional level. By binding Protein kinase Cα (PKCα), a classical regulating factor of Bcl-2, NDRG1 enhanced the ubiquitination and degradation of Bcl-2, thus promoting apoptosis in CRC cells. In addition, NDRG1 inhibited tumor growth and promoted apoptosis in mouse xenograft model. In conclusion, NDRG1 promotes oxaliplatin-triggered apoptosis in colorectal cancer. Therefore, colorectal cancer patients can be stratified by the expression level of NDRG1. NDRG1-positive patients may benefit from oxaliplatin-containing chemotherapy regimens whereas those with negative NDRG1 expression should avoid the usage of this cytotoxic drug.

Highlights

Preoperative chemoradiation therapy (CRT) followed by total mesorectal excision (TME) has been currently considered as the standard treatment strategy for locally advanced rectal cancer (LARC) [1,2,3]
N-myc downstream-regulated gene1 (NDRG1) positively correlated to the downstaging rate and prognosis of LARC patients receiving neoadjuvant chemotherapy
To evaluate the potential effect of NDRG1 on the efficacy of oxaliplatin-based chemotherapy, total RNA was extracted from cancer tissues and subjected to reverse transcription-polymerase chain reaction (RT-PCR)

Summary

Introduction

Preoperative chemoradiation therapy (CRT) followed by total mesorectal excision (TME) has been currently considered as the standard treatment strategy for locally advanced rectal cancer (LARC) [1,2,3]. Several randomized trials comparing the efficacy and toxicities of CRT with or without oxaliplatin (L-OHP), as the preoperative treatment for locally advanced rectal cancer have been reported [4,5,6,7]. Apoptosis is a morphologically and molecularly distinct form of programmed cell death. One of the most important advances in cancer research is the recognition that apoptosis is crucially involved in the regulation of tumor formation and critically determines chemotherapy treatment response [12, 14, 15]. Understanding of the molecular events that regulate apoptosis in response to anticancer chemotherapy, and how cancer cells evade apoptotic death provides novel insights for a more rational approach to develop molecular targeted therapies for combating cancer

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