SHP2 mutations promote glycolysis and inhibit apoptosis via PKM2/hnRNPK signaling in colorectal cancer
Bo Zhou,
Zhuoyang Fan,
Guodong He,
Wei Zhang,
Guowei Yang,
Lechi Ye,
Jianmin Xu,
Rong Liu
Affiliations
Bo Zhou
Department of Interventional Radiology, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Shanghai Institute of Medical Imaging, Shanghai 200032, China
Zhuoyang Fan
Department of Interventional Radiology, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Shanghai Institute of Medical Imaging, Shanghai 200032, China
Guodong He
Department of Colorectal Surgery, Zhongshan Hospital Fudan University, Shanghai 200032, China; Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive Technology, Shanghai 200032, China
Wei Zhang
Department of Interventional Radiology, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Shanghai Institute of Medical Imaging, Shanghai 200032, China
Guowei Yang
Department of Interventional Radiology, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Shanghai Institute of Medical Imaging, Shanghai 200032, China
Lechi Ye
Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Corresponding author
Jianmin Xu
Department of Colorectal Surgery, Zhongshan Hospital Fudan University, Shanghai 200032, China; Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive Technology, Shanghai 200032, China; Corresponding author
Rong Liu
Department of Interventional Radiology, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Shanghai Institute of Medical Imaging, Shanghai 200032, China; Corresponding author
Summary: Colorectal cancer (CRC) is one of the most common gastrointestinal tumors. Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) mutations occur in human solid tumors, including CRC. However, the function and underlying mechanism in CRC have not been well characterized. We demonstrated that the SHP2D61Y and SHP2E76K mutations occurred in CRC tissues, and these mutations promoted CRC cell proliferation, migration/invasion, and reduced CDDP-induced cell apoptosis in vitro and in vivo. Mechanistically, SHP2D61Y and SHP2E76K promote glycolysis by accelerating pyruvate kinase M2 (PKM2) nuclear translocation through mechanism beyond ERK activation. PKM2-IN-1 attenuates PKM2-dependent glycolysis and reduce glucose uptake, lactate production, and ATP levels promoted by SHP2D61Y and SHP2E76K in CRC cells. Furthermore, PKM2 upregulates heterogeneous nuclear ribonucleoprotein K (hnRNPK) expression and increases CRC cell proliferation and migration/invasion via regulating hnRNPK ubiquitination. These findings provide evidence that SHP2D61Y and SHP2E76K regulate CDDP-induced apoptosis, glucose metabolism, and CRC migration/invasion through PKM2 nuclear translocation and PKM2/hnRNPK signaling.
