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Targeting oxidative pentose phosphate pathway prevents recurrence in mutant Kras colorectal carcinomas.
- Source :
- PLoS Biology; 8/28/2019, Vol. 17 Issue 8, p1-28, 28p, 2 Diagrams, 5 Graphs
- Publication Year :
- 2019
-
Abstract
- 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]
Details
- Language :
- English
- ISSN :
- 15449173
- Volume :
- 17
- Issue :
- 8
- Database :
- Complementary Index
- Journal :
- PLoS Biology
- Publication Type :
- Academic Journal
- Accession number :
- 138304071
- Full Text :
- https://doi.org/10.1371/journal.pbio.3000425