Abstract 186P
Background
Pyruvate kinase M2 (PKM2), the final rate-limiting enzyme in glycolysis, exists in a dynamic population of monomer, dimer and tetramer that determine its pyruvate kinase activity. However, the roles of oncoproteins, such as the cancerous inhibitor of protein phosphatase PP2A (CIP2A) that is overexpressed in most human malignancies, in PKM2 dimer-tetramer switching remain largely unknown.
Methods
The CIP2A interacting proteins were analyzed by mass spectrometry sequencing and verified in cancer cells. The effects of CIP2A on PKM2 dimer-tetramer switching and cell metabolism were evaluated by size-exclusion chromatography and seahorse metabolic assays. The expression of CIP2A and phosphorylated PKM2 S287 in non-small cell lung cancer (NSCLC) was detected by immunohistochemistry assay, and the therapeutic efficacy of agents targeting CIP2A and PKM2 was tested in NSCLC murine model.
Results
We reported that CIP2A could directly interact with PKM2 in NSCLC cells. CIP2A induced formation of PKM2 tetramer by phosphorylation of PKM2 at Ser287, which was shown to be critical for maintaining the tetramer state and activity of PKM2. In contrast, depletion of CIP2A promoted PKM2 dimer accumulation and translocation into the nucleus, resulting in the enhancement of glycolysis. Pharmacological inhibition of glycolysis or activation of PKM2 synergistically inhibited NSCLC cell growth when combined with CIP2A-targeting natural compound celastrol both in vitro and in vivo.
Conclusions
These results demonstrated that CIP2A determines PKM2 tetramer-dimer transition and controls the metabolic reprogramming of NSCLC cells.
Legal entity responsible for the study
The authors.
Funding
This work was supported by the National Key Research and Development Program of China (No. 2020YFA0803300), the Key Project of the National Natural Science Foundation of China (81830093), the CAMS Innovation Fund for Medical Sciences (CIFMS; Nos. 2021-RC310-003, 2020-RC310-002), CAMS Initiative for Innovative Medicine (2021-1-I2M-012), and the National Natural Science Foundation of China8 (2073092 and 81802796).
Disclosure
All authors have declared no conflicts of interest.