Abstract
The M2 isoform of pyruvate kinase (PKM2), as a key glycolytic enzyme, plays important roles in tumorigenesis and chemotherapeutic drug resistance. However, the intricate mechanism of PKM2 as a protein kinase regulating breast cancer progression and tamoxifen resistance needs to be further clarified. Here, we reported that PKM2 controls the expression of survivin by phosphorylating c-Myc at Ser-62. Functionally, PKM2 knockdown suppressed breast cancer cell proliferation and migration, which could be rescued by overexpression of survivin. Interestingly, we found that the level of PKM2 expression was upregulated in the tamoxifen resistant breast cancer cells MCF-7/TAMR, and knockdown of PKM2 sensitized the cells to 4-hydroxytamoxifen (4OH-T). In addition, the elevated level of PKM2 correlates with poor relapse-free survival in breast cancer patients treated with tamoxifen. Overall, our findings demonstrated that PKM2–c-Myc–survivin cascade regulated the proliferation, migration and tamoxifen resistance of breast cancer cells, suggesting that PKM2 represents a novel prognostic marker and an attractive target for breast cancer therapeutics, and that PKM2 inhibitor combined with tamoxifen may be a promising strategy to reverse tamoxifen resistance in breast cancer patients.
Highlights
Pyruvate kinase isoform M2 (PKM2), one of the isoenzymes of pyruvate kinase (PK) (Yang and Lu, 2013), is a key glycolytic enzyme overexpressed in cancer cells (Luo and Semenza, 2012), which controls the terminal rate-limiting step of glycolysis by catalyzing the transform of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP) (Hamanaka and Chandel, 2011)
We reported for the first time that PKM2-c-Myc-survivin signaling cascade promoted breast cancer cell proliferation, migration, tamoxifen resistance (Figure 6H), and inhibition of PKM2 blocked cancer progression, and enhanced tamoxifen efficacy in MCF-7 and MCF-7 resistant cells
It was reported that the PKM2–b-catenin interaction leaded to increased binding of b-catenin to the promoter region of c-Myc (Yang et al, 2011)
Summary
Pyruvate kinase isoform M2 (PKM2), one of the isoenzymes of pyruvate kinase (PK) (Yang and Lu, 2013), is a key glycolytic enzyme overexpressed in cancer cells (Luo and Semenza, 2012), which controls the terminal rate-limiting step of glycolysis by catalyzing the transform of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP) (Hamanaka and Chandel, 2011). Previous reports suggested that PKM2 affects cell proliferation, migration, invasion, apoptosis, and cell cycle progression of tumors, including breast cancer, prostate. There have been increasing evidence pointing to the non-glycolytic function of PKM2 in tumor cells. The role of PKM2 as a protein kinase in the regulation of tumor progression in breast cancer remains to be further identified. Studies have shown that PKM2 is highly correlated with drug resistance. It has been demonstrated recently that NAMPT promotes tamoxifen resistance via regulation of the PKM2 translocation (Ge et al, 2019). The specific mechanism and role of PKM2 in regulating breast cancer tamoxifen resistance remains unknown
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