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

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.

Targeting Glucose Transporters for Breast Cancer Therapy: The Effect of Natural and Synthetic Compounds

“…This sesquiterpenoid bioactive compound is secreted by beetles of the family of Meloidae [155]. Although it has been available for almost a century, its use has not been approved due to its high toxicity to the gastrointestinal tract.…”

“…It was concluded that cantharidin inhibits nuclear translocation of pyruvate kinase isoform M2 (PKM2), which promotes the transcription of GLUT1. So, cantharidin interferes with the glycolytic metabolic loop between GLUT1 and PKM2 [155] (Table 3).…”

The Flick of a Switch: Conferring Survival Advantage to Breast Cancer Stem Cells Through Metabolic Plasticity

“…Glycolic metabolite methylglyoxal promotes extracellular matrix remodeling and activation of the pro-migratory signaling pathway, MEK/ERK/SMAD1 in estrogen receptor-positive (ER+) and TNBC cell lines (7). Inversely, treatment of breast cancer cells and xenografts with natural compound cantharidin inhibited migration, invasion, angiogenesis, and metastasis by increasing oxygen consumption and suppressing aerobic glycolysis (8). Furthermore, increased oxygen consumption and dependence on oxidative metabolism through the expression of good prognostic marker B-cell lymphoma two associated death promoter (BAD) resulted in large but non-aggressive breast tumors (9).…”

Anticancer Attributes of Cantharidin: Involved Molecular Mechanisms and Pathways

“…Divulging this mechanism, they highlighted that CTD can inhibit pyruvate kinase (PK), which causes blockage in pyruvate kinase M2 (PKM2) translocation to the nucleus. This process leads to the downregulation of GLUT1/PKM2 loop which is essential for glucose transport and glycolytic metabolism [ 17 ]. CTD attenuated proliferation and migration of pancreatic cancer cells as a consequence of β-catenin-directed repression of Wnt/β-catenin signaling pathway [ 59 ].…”

“…The anticarcinogenic efficacy of this terpenoid toxin was first highlighted by Chen et al around four decades back (1980) [ 16 ]. After it, further researches were conducted to elucidate its antitumor effects and finally, it has been revealed that its anticancer activity is mainly due to the inhibition of protein phosphatase 1 (PP1) and protein phosphatase type 2A (PP2A) [ 17 ]. Moreover, it has also been proven that CTD can inhibit expression level of HSP70 and BAG3 proteins by preventing heat shock transcription factor 1 (HSF-1) binding to its promoter [ 18 , 19 ].…”