(+)‐Usnic Acid Inhibits Migration of c‐KIT Positive Cells in Human Colorectal Cancer

Abstract

Inhibition of tumor cell migration is a treatment strategy for patients with colorectal cancer (CRC). SCF‐dependent activation of c‐KIT is responsible for migration of c‐KIT positive [c‐KIT(+)] cells of CRC. Drug resistance to Imatinib Mesylate (c‐KIT inhibitor) has emerged. Inhibition of mTOR can induce autophagic degradation of c‐KIT. (+)‐usnic acid [(+)‐UA], isolated from lichens, has two major functions including induction of proton shuttle and targeting inhibition of mTOR. To reduce hepatotoxicity, the treatment concentration of (+)‐UA should be lower than 10 μ M. HCT116 cells and LS174 cells were employed to investigate the inhibiting effect of (+)‐UA (<10 μ M) on SCF‐mediated migration of c‐KIT(+) CRC cells. HCT116 cells were employed to investigate the molecular mechanisms. The results indicated that firstly, 8 μ M (+)‐UA decreased ATP content via uncoupling; secondly, 8 μ M (+)‐UA induced mTOR inhibition, thereby mediated activation suppression of PKC‐A, and induced the autophagy of the completed autophagic flux that resulted in the autophagic degradation and transcriptional inhibition of c‐KIT and the increase in LDH release; ultimately, 8 μ M (+)‐UA inhibited SCF‐mediated migration of CRC c‐KIT(+) cells. Taken together, 8 μ M could be determined as the effective concentration for (+)‐UA to inhibit SCF‐mediated migration of CRC c‐KIT(+) cells.