%0 Journal Article
%T Targeting oxidative pentose phosphate pathway prevents recurrence in mutant Kras colorectal carcinomas
%A ChunFang Gao
%A Dong Wei
%A QingQuan Li
%A Tao Chen
%A Wei Zhang
%A WenChao Gao
%A XiuJuan Liu
%A YuTing Xu
%A ZhiQian Hu
%A ZunGuo Du
%J -
%D 2019
%R 10.1371/journal.pbio.3000425
%X Recurrent tumors originate from cancer stem cells (CSCs) that survive conventional treatments. CSCs consist of heterogeneous subpopulations that display distinct sensitivity to anticancer drugs. Such a heterogeneity presents a significant challenge in preventing tumor recurrence. In the current study, we observed that quiescent CUB-domain¨Ccontaining protein 1 (CDCP1)+ CSCs are enriched after chemotherapy in mutant Kirsten rat sarcoma viral oncogene homolog (Kras) colorectal carcinomas (CRCs) and serve as a reservoir for recurrence. Mechanistically, glucose catabolism in CDCP1+ CSCs is routed to the oxidative pentose phosphate pathway (PPP); multiple cycling of carbon backbones in the oxidative PPP potentially maximizes NADPH reduction to counteract chemotherapy-induced reactive oxygen species (ROS) formation, thereby allowing CDCP1+ CSCs to survive chemotherapeutic attack. This is dependent on silent mating type information regulation 2 homolog 5 (Sirt5)-mediated inhibition of the glycolytic enzyme triosephosphate isomerase (TPI) through demalonylation of Lys56. Blocking demalonylation of TPI at Lys56 increases chemosensitivity of CDCP1+ CSCSs and delays recurrence of mutant Kras CRCs in vivo. These findings pinpoint a new therapeutic approach for combating mutant Kras CRCs
%K Colorectal cancer
%K Cancer stem cells
%K Cancer treatment
%K Cell metabolism
%K Drug metabolism
%K Phosphates
%K Glycolysis
%K Carcinomas
%U https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000425