Targeting oxidative pentose phosphate pathway prevents recurrence in mutant Kras colorectal carcinomas.
- Resource Type
- Article
- Authors
- Gao, WenChao; Xu, YuTing; Chen, Tao; Du, ZunGuo; Liu, XiuJuan; Hu, ZhiQian; Wei, Dong; Gao, ChunFang; Zhang, Wei; Li, QingQuan
- Source
- PLoS Biology. 8/28/2019, Vol. 17 Issue 8, p1-28. 28p. 2 Diagrams, 5 Graphs.
- Subject
- *PENTOSE phosphate pathway
*CANCER stem cells
*TRIOSE-phosphate isomerase
*CARCINOMA
*CELL physiology
- Language
- ISSN
- 1544-9173
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–containing 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. [ABSTRACT FROM AUTHOR]