TBC1D8 Amplification Drives Tumorigenesis through Metabolism Reprogramming in Ovarian Cancer

Theranostics
Min ChenGuang-Rong Yan

Abstract

Cancer cells undergo metabolic reprogramming to support their energy demand and biomass synthesis. However, the mechanisms driving cancer metabolism reprogramming are not well understood. Methods: The differential proteins and interacted proteins were identified by proteomics. Western blot, qRT-PCR and IHC staining were used to analyze TBC1D8 levels. In vivo tumorigenesis and metastasis were performed by xenograft tumor model. Cross-Linking assays were designed to analyze PKM2 polymerization. Lactate production, glucose uptake and PK activity were determined. Results: We established two aggressive ovarian cancer (OVCA) cell models with increased aerobic glycolysis. TBC1D8, a member of the TBC domain protein family, was significantly up-regulated in the more aggressive OVCA cells. TBC1D8 is amplified and up-regulated in OVCA tissues. OVCA patients with high TBC1D8 levels have poorer prognoses. TBC1D8 promotes OVCA tumorigenesis and aerobic glycolysis in a GAP activity-independent manner in vitro and in vivo. TBC1D8 bound to PKM2, not PKM1, via its Rab-GAP TBC domain. Mechanistically, TBC1D8 binds to PKM2 and hinders PKM2 tetramerization to decreases pyruvate kinase activity and promote aerobic glycolysis, and to promote the nucl...Continue Reading

Citations

Feb 13, 2021·Journal of Experimental & Clinical Cancer Research : CR·Hui-Er ZhuHui Chen

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Methods Mentioned

BETA
acetylation
PCR
chips
xenograft
co-IP
Assay
xenografts
GTPase
nuclear translocation

Software Mentioned

Prism
Mascot
Protein Pilot
SPSS

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