Synthetic lethality of glutaminolysis inhibition, autophagy inactivation and asparagine depletion in colon cancer

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// Jiaqiu Li 1, 2 , Ping Song 1 , Liyuan Zhu 2 , Neelum Aziz 1 , Qiyin Zhou 1 , Yulong Zhang 2 , Wenxia Xu 2 , Lifeng Feng 2 , Dingwei Chen 3 , Xian Wang 1 and Hongchuan Jin 2 1 Department of Medical Oncology, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China 2 Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China 3 Department of Surgery, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China Correspondence to: Dingwei Chen, email: dwyf@hotmail.com Xian Wang, email: wangxzju@163.com Hongchuan Jin, email: jinhc@zju.edu.cn Keywords: colorectal cancer, glutaminolysis, glutamine, synthetic lethality Received: December 21, 2016 Accepted: March 17, 2017 Published: April 05, 2017 ABSTRACT Cancer cells reprogram metabolism to coordinate their rapid growth. They addict on glutamine metabolism for adenosine triphosphate generation and macromolecule biosynthesis. In this study, we report that glutamine deprivation retarded cell growth and induced prosurvival autophagy. Autophagy inhibition by chloroquine significantly enhanced glutamine starvation induced growth inhibition and apoptosis activation. Asparagine deprivation by L-asparaginase exacerbated growth inhibition induced by glutamine starvation and autophagy blockage. Similar to glutamine starvation, inhibition of glutamine metabolism with a chemical inhibitor currently under clinical evaluation was synthetically lethal with chloroquine and L-asparaginase, drugs approved for the treatment of malaria and leukemia, respectively. In conclusion, inhibiting glutaminolysis was synthetically lethal with autophagy inhibition and asparagine depletion. Therefore, targeting glutaminolysis could be a promising approach for colorectal cancer treatment.