Open AccessSynthetic lethality of glutaminolysis inhibition, autophagy inactivation and asparagine depletion in colon cancer
Author(s) -
Jiaqiu Li,
Ping Song,
Liyuan Zhu,
Neelum Aziz,
Qing Zhou,
Yulong Zhang,
Wenxia Xu,
Lifeng Feng,
Dingwei Chen,
Xian Wang,
Hongchuan Jin
Publication year - 2017
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.16844
Subject(s) - glutaminolysis , synthetic lethality , glutamine , autophagy , glutaminase , cancer research , cancer cell , medicine , cancer , chemistry , apoptosis , biochemistry , amino acid , dna repair , gene
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.