Blocking Dimeric Pyruvate Kinase M2 Transformation and Nuclear Translocation Leading to Suppression of Aerobic Glycolysis Mediates Beta-Elemene Inhibition of Breast Cancer Metastasis

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Pyruvate kinase M2 (PKM2) plays a central role in regulating aerobic glycolysis and is considered as a potential target for cancer therapy. However, its role in cancer metastasis is rarely known. Here, we found a tight relationship between PKM2 and breast cancer metastasis, which is demonstrated by the finding that beta-elemene (β-elemene), an approved drug for complementary cancer therapy, exerted distinct anti-metastatic activity dependent on PKM2. The results indicated thatβ-elemene inhibited breast cancer cell migration, invasion and angiogenesis. β-elemene also inhibited the process of glycolysis, and decreased the utilization of glucose and the production of pyruvate and lactate through suppressing pyruvate kinase activity by modulating the transformation of dimeric and tetrameric forms of PKM2, which was reversed in part by fructose-1,6-bisphosphate (FBP) or L-cysteine. Our further analysis revealed that β-elemene suppressed aerobic glycolysis through inhibiting the nuclear transportation of PKM2 and the expression of GLUT1, MCT1, MCT4 and LDHA by influencing the expression of importin α5. Additionally, β-elemene remarkably inhibited the breast cancer metastases in lung and liver and selectively influenced the glycolysis of the lung and liver metastatic foci in mouse models. Taken together, tetrameric transformation and nuclear translocation of PKM2 are essential for cancer metastasis, and β-elemene inhibits breast cancer metastasis via blocking aerobic glycolysis induced by dimeric PKM2 transformation and EGFR-importin α5 mediated PKM2 nuclear translocation, being a promising anti-metastatic agent. Funding Statement: The work was supported by National Natural Science Foundation of China (No. 81673648, 81673725, 81573859, 81603339), Natural Science Foundation of Higher School of Jiangsu Province (17KJA360003), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: All animal studies were approved by the Animal Care and Use Committee of Nanjing University of Chinese Medicine. All mouse experimental procedures were performed in accordance with the Regulations for the Administration of Affairs Concerning Experimental Animals approved by the State Council of People’s Republic of China.