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

• Published in: PLoS biology 2019-08, Vol.17 (8), p.e3000425-e3000425
• Main Authors: Gao, WenChao, Xu, YuTing, Chen, Tao, Du, ZunGuo, Liu, XiuJuan, Hu, ZhiQian, Wei, Dong, Gao, ChunFang, Zhang, Wei, Li, QingQuan
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Neoplasm - metabolism; Antineoplastic Agents - pharmacology; Antineoplastic drugs; Antitumor agents; Biology and Life Sciences; Cancer; Cancer cells; Cancer therapies; Carbon cycle; Care and treatment; Catabolism; Cell Adhesion Molecules - metabolism; Cell cycle; Cell Line, Tumor; Chemotherapy; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Cytotoxicity; Drug resistance; Epidermal growth factor; Funding; Glycolysis; Health aspects; Heterogeneity; Homology; Hospitals; Humans; K-Ras protein; Kinases; Medicine and Health Sciences; Metabolism; Metabolites; Mice; Mice, Inbred BALB C; Mice, Transgenic; Mutants; Mutation; NADP; NADP - metabolism; Neoplastic Stem Cells - physiology; Oxidation-Reduction; Oxidative Stress - drug effects; Pathology; Patient outcomes; Pentose; Pentose phosphate pathway; Pentose Phosphate Pathway - genetics; Pentose Phosphate Pathway - physiology; Phase transitions; Phosphates; Physical Sciences; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Relapse; Sarcoma; Sirtuins - metabolism; Software; Stem cell transplantation; Stem cells; Subpopulations; Surgery; Triose-phosphate isomerase; Tumors
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3000425

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.