Cryptolepine suppresses breast adenocarcinoma via inhibition of HIF-1 mediated glycolysis

As a characteristic transcription factor in solid tumors, hypoxia inducible factor-1 (HIF-1) acts as a master regulator in breast cancer progression. Cryptolepine, as a natural alkaloid, noticeably inhibited HIF-1 transcriptional activity and decreased the protein expression of hypoxia-induced HIF-1 alpha in breast cancer cells. Further study showed that cryptolepine blocked HIF-1-mediated glycolysis and suppressed the expression of multiple glycolysis enzymes, resulting in a decrease in ATP production in hypoxic T47D and 4T1 cells. Meanwhile, cryptolepine displayed potent suppressive effect on tumor growth in a dose-dependent manner. In 4T1 tumor xenografts, cryptolepine reduced HIF-1 alpha protein expression, and thus decreased the levels of both lactate acid and ATP productions. The mechanistic study revealed that cryptolepine could effectively suppress the process of HIF-1 alpha mRNA translation rather than transcription, which was attributed to the inhibition on the phosphorylation of eIF4E regulated by both MAPK and mTOR signaling pathways. Collectively, current findings suggested that cryptolepine possesses the potential to treat breast cancers by modulating HIF-1 both in vitro and in vivo.

Automated summary

The current study found that Cryptolepine possesses the potential to treat breast cancer by inhibiting HIF-1 activity and decreasing HIF-1α protein expression. It suppresses tumor growth by blocking HIF-1-mediated glycolysis and reducing ATP production. Mechanistically, Cryptolepine inhibits the phosphorylation of eIF4E to suppress HIF-1α mRNA translation.