Breaking Glucose Transporter 1/Pyruvate Kinase M2 Glycolytic Loop Is Required for Cantharidin Inhibition of Metastasis in Highly Metastatic Breast Cancer.

Yanhong Pan,Meng Wang,Zhonghong Wei,Qian Zheng,Wenxing Chen,Aiyun Wang,Yin Lu,Qi Jia,Wenting Ni,Suyun Yu

doi:10.3389/fphar.2019.00590

Abstract

Aerobic glycolysis plays a decisive role in cancer growth. However, its role in cancer metastasis was rarely understood. Cantharidin a natural compound from an arthropod insect cantharis exerts potent anticancer activity. Here we found cantharidin possesses significant anti-metastatic activity on breast cancer dependent on inhibition of aerobic glycolysis. Cantharidin indicates significant inhibition on migration and invasion of breast cancer cells, angiogenesis in vitro, and inhibits breast cancer cells metastasizing to liver and lung in vivo. Subsequent results revealed that cantharidin decreases the extracellular acidification rates (ECAR) but increases the oxygen consumption rates (OCR) in high metastatic cells, leading to suppression of aerobic glycolysis. This was considered to be due to inhibiting the activity of pyruvate kinase (PK) and further blocking pyruvate kinase M2 (PKM2) translocation in nucleus. Fructose-1,6-bisphosphate (FBP) and L-cysteine can significantly reverse cantharidin inhibition on breast cancer cell migration, invasion, and PKM2 translocation. Furthermore, glucose transporter 1 (GLUT1) forming a metabolic loop with PKM2 is downregulated, as well as epidermal growth factor receptor (EGFR), the regulator of the glycolytic loop. Totally, cantharidin inhibits the PKM2 nuclear translocation and breaks GLUT1/PKM2 glycolytic loop, resulting in aerobic glycolysis transformation to oxidation and subsequent reversing the metastases in breast cancer. Based on inhibiting multi signals mediated aerobic glycolysis, cantharidin could be prospectively used for prevention of metastasis in breast cancer patients.

Highlights

According to the latest global cancer statistics in 2018, the incidence of breast cancer still following the lung cancer is on the second place and its 6.6% mortality lies first among the cancers of the female (Bray et al, 2018)
This study demonstrated that cantharidin can block the multimetastatic processes
pyruvate kinase (PK) plays a pivotal role in the final step of glycolysis and catalyzes PEP to form pyruvate by transferring a phosphate group

Summary

Introduction

According to the latest global cancer statistics in 2018, the incidence of breast cancer still following the lung cancer is on the second place and its 6.6% mortality lies first among the cancers of the female (Bray et al, 2018). The Mylabris cichorii Linnaeus and Mylabris phaleratus Pallas are the most common blister beetles used in traditional Chinese medicine (Wu et al, 2018) Their dried insect bodies were used for more than 2,000 years due to their efficacy in activating blood and removing stasis, treating warts and molluscum through topical administration. The critical molecular pathways by which cantharidin induces cancer growth inhibition and cell death were found to be more complicated. Cantharidin inhibits cancer cell migration and invasion via activating the IKKα/ IκBα/NF-κB pathway by inhibiting PP2A activity (Zhou et al, 2018) or suppressing the MMPs (Ji et al, 2015; Shen et al, 2015), suggesting it may be a potential anti-metastatic compound.

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Conclusion