Background:The protein-serine/threonine kinase PIM2 regulates glycolysis, but the mechanism is not fully elucidated. Results: PIM2 interacts with PKM2 and phosphorylates PKM2 on the Thr-454 residue. Conclusion: This phosphorylation of PKM2 increases glycolysis and proliferation in cancer cells. Significance: PIM2-dependent phosphorylation of PKM2 is critical for regulating the Warburg effect in cancer, highlighting PIM2 as a potential therapeutic target.
Pyruvate kinase M2 (PKM2), which is predominantly expressed in most cancers, plays a key role in the Warburg effect. However, how PKM2 functions as a tumor supportive protein has not been fully elucidated. Here, we identified tristetraprolin (TTP), an AU-rich, element-binding protein that regulates mRNA stability, as a new binding partner of PKM2. Our data reveal that PKM2 suppresses TTP protein levels by promoting its phosphorylation, ubiquitination, and proteasome degradation, reducing its mRNA turnover ability and ultimately impairing cell viability in breast cancer cells. The p38/mitogen-activated protein kinase (MAPK) pathway might be involved in PKM2-mediated TTP degradation, while treatment with the p38 inhibitor or siRNA abolished PKM2-induced TTP protein degradation. These findings demonstrate that PKM2–TTP association is crucial for regulating breast cancer cell proliferation and is therefore a potential therapeutic target in cancer.
Pyruvate kinase M2 (PKM2) is predominantly expressed in cancers, which is considered as a key regulator of the Warburg effect. In this study, HSP40 was identified as a novel binding partner of PKM2. HSP40-PKM2 association destabilized PKM2 protein through HSC70. In the presence of HSP40, PKM2 protein level and PKM2-mediated PDK1 expression were down-regulated. Moreover, HSP40 was involved in regulating glucose metabolism on PKM2 dependent way and at the mean time had an effect on mitochondrial oxygen respiration. In line with inhibition effect of HSP40 on glycolysis, the growth of cancer cells was inhibited by HSP40.Our data provided a new regulation mechanism of PKM2, which suggested a new therapeutic target for cancer therapy.
To survive under hypoxic conditions, cancer cells remodel glucose metabolism to support tumor progression. HIF transcription factor is essential for cellular response to hypoxia. The underlying mechanism how HIF is constitutively activated in cancer cells remains elusive. In the present study, we characterized a regulatory feedback loop between HIF-1α and PIM2 in HepG2 cells. Serine/threonine kinase proto-oncogene PIM2 level was induced upon hypoxia in a HIF-1α-mediated manner in cancer cells. HIF-1α induced PIM2 expression via binding to the hypoxia-responsive elements (HREs) of the PIM2 promoter. In turn, PIM2 interacted with HIF-1α, especially a transactivation domain of HIF-1α. PIM2 as a co-factor but not an upstream kinase of HIF-1α, enhanced HIF-1α effect in response to hypoxia. The positive feedback loop between PIM2 and HIF-1α was correlated with glucose metabolism as well as cell survival in HepG2 cells. Such a regulatory mode may be important for the adaptive responses of cancer cells in antagonizing hypoxia during cancer progression.
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