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 μM. HCT116 cells and LS174 cells were employed to investigate the inhibiting effect of (+)-UA (<10 μM) on SCF-mediated migration of c-KIT(+) CRC cells. HCT116 cells were employed to investigate the molecular mechanisms. The results indicated that firstly, 8 μM (+)-UA decreased ATP content via uncoupling; secondly, 8 μM (+)-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 μM (+)-UA inhibited SCF-mediated migration of CRC c-KIT(+) cells. Taken together, 8 μM could be determined as the effective concentration for (+)-UA to inhibit SCF-mediated migration of CRC c-KIT(+) cells.
Highlights
Colorectal cancer (CRC) is characterized by the fourth most familiar cause of cancer-related death in the world [1]
The results indicated that the treatment with 8 μM (+)-UA mediated the downregulation of cell growth factor receptor Kit (c-KIT) and p-c-KIT in 48 hours and attenuated SCF-mediated activation of protein kinase C alpha type (PKC-A) in 24 or 48 hours, respectively
SCF-dependent activation of c-KIT is responsible for migration of c-KIT(+) CRC cells [6]
Summary
Colorectal cancer (CRC) is characterized by the fourth most familiar cause of cancer-related death in the world [1]. Inhibition of mTOR may probably suppress SCF-mediated migration of c-KIT(+) CRC cells via inducing the autophagic degradation and transcriptional inhibition of c-KIT. As the end results of targeting inhibition of mTOR and induction of proton shuttle, the treatments of different cancer cell lines with 12.5-100 μM of (+)-UA can effectively mediate autophagic death or apoptosis in a time and dose dependent manner [18, 19, 21, 22]. There is a functional synergy between targeting inhibition of mTOR and induction of proton shuttle that probably endows (+)UA with the ability to inhibit SCF-mediated migration of cKIT(+) CRC cells. HCT116 cells and LS174 cells would be employed to investigate and confirm the inhibiting effect of (+)-UA (
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