Abstract
Pyruvate kinase M2 (PKM2) is known to promote tumourigenesis through dimer formation of p-PKM2Y105. Here, we investigated whether SH2-containing protein tyrosine phosphatase 1 (SHP-1) decreases p-PKM2Y105 expression and, thus, determines the sensitivity of sorafenib through inhibiting the nuclear-related function of PKM2. Immunoprecipitation and immunoblot confirmed the effect of SHP-1 on PKM2Y105 dephosphorylation. Lactate production was assayed in cells and tumor samples to determine whether sorafenib reversed the Warburg effect. Clinical hepatocellular carcinoma (HCC) tumor samples were assessed for PKM2 expression. SHP-1 directly dephosphorylated PKM2 at Y105 and further decreased the proliferative activity of PKM2; similar effects were found in sorafenib-treated HCC cells. PKM2 was also found to determine the sensitivity of targeted drugs, such as sorafenib, brivanib, and sunitinib, by SHP-1 activation. Significant sphere-forming activity was found in HCC cells stably expressing PKM2. Clinical findings suggest that PKM2 acts as a predicting factor of early recurrence in patients with HCC, particularly those without known risk factors (63.6%). SHP-1 dephosphorylates PKM2 at Y105 to inhibit nuclear function of PKM2 and determines the efficacy of targeted drugs. Targeting PKM2 by SHP-1 might provide new therapeutic insights for patients with HCC.
Highlights
Abnormal glucose metabolism enhances biosynthesis and cell proliferation and is, a vital component of tumorigenesis
We assessed the affinity of Pyruvate kinase M2 (PKM2) to the substrate trapping mutant of SH2-containing protein tyrosine phosphatase 1 (SHP-1) (SHP-1-catalytic-dead SHP1 (C/S)), in which the conserved C453 residue was mutated to generate an inactive enzyme that locks the substrate in its catalytic pocket
PKM2 is expressed in tumor cells and plays an important role in the shift to aerobic glycolysis associated with tumor progression. [3, 23] Loss of PKM2 is known to extend disease latency of myeloid leukemia in mice
Summary
Abnormal glucose metabolism enhances biosynthesis and cell proliferation and is, a vital component of tumorigenesis. The nuclear location of PKM2 is associated with cell proliferation. In addition to its glycolytic function, PKM2 acts as a protein www.impactjournals.com/oncotarget kinase targeting histone H3 [7] and STAT3 [8] to promote tumorigenesis and gene transcription. Several growth signals, such as EGF [7, 9,10,11,12] and FGF [5, 13], have been reported to enhance the nucleus-dependent proliferative activity of PKM2 by protein tyrosine phosphorylation. Here, we explored the hypothesis that the protein tyrosine phosphatase (PTP), which regulates the nucleus-dependent PKM2, contributes to the sensitivity of targeted drugs by reversing the nuclear location of PKM2
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