Targeting oxidative pentose phosphate pathway prevents recurrence in mutant Kras colorectal carcinomas.

Targeting oxidative pentose phosphate pathway prevents recurrence in mutant Kras colorectal carcinomas.

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Recurrent tumors originate Self-Help Aids 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 Lighting LED mutant Kras CRCs in vivo.These findings pinpoint a new therapeutic approach for combating mutant Kras CRCs.