Microcolin A, a lipopeptide from marine cyanobacteria, suppresses the non-small cell lung carcinoma by regulating the C-terminal of Hsp90α and ROS/ERK signaling pathways.

Lung cancer remains to be the leading cause of cancer-related mortality worldwide, with non-small cell lung carcinoma (NSCLC) accounting for approximately 85% and the five-year survival rate below 20%. Microcolin A (Mic A), a lipopeptide derived from marine cyanobacteria, exhibits significant antitumor activity, however, its underlying mechanism is unclear. Hsp90 is highly expressed in various cancer tissues and positively correlated with tumor progression and aggressiveness. Existing studies have shown that most Hsp90 inhibitors target the N-terminal ATP-binding pockets, however, the clinical trials of the relevant candidate drugs have been halted or postponed for insufficient stratification and side effects. In contrast, targeting the C-terminal domain of Hsp90 may be a more promising route to develop the anti-cancer drug. In this study, we find that Hsp90α is a potential target for Mic A, which could target the C-terminal of Hsp90α and suppress its expression in NSCLC cells. Mic A could also induce the apoptosis of NSCLC cells through reactive oxygen species (ROS) and ERK phosphorylation pathways, and the autophagy process may also be involved in the mechanism. In the NSCLC xenograft tumor model, Mic A could significantly reduce the growth of xenograft tumors by reducing Hsp90 and upregulating ERK phosphorylation. Overall, our research provides a broader perspective for a deeper understanding of the development of anti-tumor drugs targeting Hsp90, and the mechanism of intracellular downstream signaling pathways. And the Mic A, a tool molecule derived from the ocean, could provide significant references for the future development of anti-NSCLC.