Synthetic lethality of glutaminolysis inhibition, autophagy inactivation and asparagine depletion in colon cancer
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Jiaqiu Li1,2, Ping Song1, Liyuan Zhu2, Neelum Aziz1, Qiyin Zhou1, Yulong Zhang2, Wenxia Xu2, Lifeng Feng2, Dingwei Chen3, Xian Wang1 and Hongchuan Jin2
1Department of Medical Oncology, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
2Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
3Department of Surgery, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
Dingwei Chen, email: [email protected]
Xian Wang, email: [email protected]
Hongchuan Jin, email: [email protected]
Keywords: colorectal cancer, glutaminolysis, glutamine, synthetic lethality
Received: December 21, 2016 Accepted: March 17, 2017 Published: April 05, 2017
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.
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