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

WenChao Gao; YuTing Xu; Tao Chen; ZunGuo Du; XiuJuan Liu; ZhiQian Hu; Dong Wei; ChunFang Gao; Wei Zhang; QingQuan Li

doi:10.1371/journal.pbio.3000425

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

PLoS Biol. 2019 Aug 28;17(8):e3000425. doi: 10.1371/journal.pbio.3000425. eCollection 2019 Aug.

Authors

WenChao Gao^{1

2}, YuTing Xu¹, Tao Chen³, ZunGuo Du^{1

4}, XiuJuan Liu^{1

4}, ZhiQian Hu², Dong Wei⁵, ChunFang Gao⁵, Wei Zhang⁶, QingQuan Li¹

Affiliations

¹ Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
² Department of General Surgery, ChangZheng Hospital, Second Military Medical University, Shanghai, China.
³ Endoscopy Center, ZhongShan Hospital, Fudan University, Shanghai, China.
⁴ Department of Pathology, HuaShan Hospital, Fudan University, Shanghai, China.
⁵ Department of Anus and Intestine Surgery, PLA Central Hospital 150, Luoyang, China.
⁶ Department of Cancer Biology, Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, United States of America.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Neoplasm / metabolism
Antineoplastic Agents / pharmacology
Cell Adhesion Molecules / metabolism
Cell Line, Tumor
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / metabolism*
Glycolysis
Humans
Mice
Mice, Inbred BALB C
Mice, Transgenic
NADP / metabolism
Neoplastic Stem Cells / physiology
Oxidation-Reduction
Oxidative Stress / drug effects
Pentose Phosphate Pathway / genetics*
Pentose Phosphate Pathway / physiology
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / metabolism
Reactive Oxygen Species / metabolism
Sirtuins / metabolism

Substances

Antigens, Neoplasm
Antineoplastic Agents
CDCP1 protein, human
Cell Adhesion Molecules
KRAS protein, human
Reactive Oxygen Species
NADP
SIRT5 protein, human
Sirtuins
Proto-Oncogene Proteins p21(ras)

Grants and funding

1. QQL received funding from the National Nature Science Foundation of China (grant numbers 81372350, 81572886, and 81874064). WCG received the funding from the National Nature Science Foundation of China (grant number 81572439). ZGD received the funding from the National Nature Science Foundation of China (grant number 81602079). The URL of the National Nature Science Foundation of China is http://www.nsfc.gov.cn/ 2. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.