Abstract 437: Hydrogen sulfide switches the glucose metabolism through sulfhydration on pyruvate kinase M2

Abstract

Abstract Cancer cells reprogram their glucose metabolism from oxidative phosphorylation to aerobic glycolysis. This metabolic transformation is partly based on the activity alterations of a rate limiting enzyme known as the pyruvate kinase M2 (PKM2), which is responsible for the conversion of phosphoenolpyruvate (PEP) into pyruvate. Attributed to its critical regulatory role. PKM2 is recognized as the pivotal enzyme in cancer glucose metabolism By reducing the enzyme activity of PKM2, cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Hydrogen sulfide (H2S), an endogenously produced gasotransmitter that acts as a critical mediator in multiple physiological processes, modifies proteins mainly through the persulfide (-SSH) bond formation, which is called sulfhydration. Our preliminary study demonstrates that H2S stimulates PKM2 sulfhydration at multiple cysteine residues, including cysteine 326, leading to the destabilization of active tetrameric PKM2 form into dimers or monomers. The PKM2 dimer/monomer further translocates into the nucleus to simulate the activation of glycolytic related genes. Blocking PKM2 sulfhydration at cysteine 326 through amino acid mutation stabilizes PKM2 tetramer and crystal structure further indicates that the tetramer organization of PKM2C326S is different from the currently known T or R states, revealing PKM2C326S as a newly identified intermediate form. Blocking PKM2 sulfhydration at cysteine 326 inhibited cell proliferation and tumor growth in xenograft mouse model. In summary, our current study illustrates that H2S-mediated sulfhydration induces the dissociation of the PKM2 tetramer, resulting in the reduced PKM2 activity and subsequently inhibits breast cancer cell proliferation and tumor growth. Targeting the sulfhydration site of PKM2 emerges as a promising therapeutic target specific for cancer metabolism. Citation Format: Po-Chen Chien, Rong-Hsuan Wang, Pin-Ru Chen, Yue-Ting Chen, Yi-Chang Chen, Yu-Hsin Chu, Chia-Chen Chien, Shao-Yun Lo, Zhong-Liang Wang, Min-Chen Tsou, Ssu-Yu Chen, Guang-Shen Chiu, Wen-Ling Chen, Yi-Hsuan Wu, Hui-Ching Wang, Shu-Yi Lin, Wen-Ching Wang, Hsing-Jien Kung, Lu-Hai Wang, Hui-Chun Cheng, Kai-Ti Lin. Hydrogen sulfide switches the glucose metabolism through sulfhydration on pyruvate kinase M2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 437.