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

Author:

Wu Wei12345ORCID,Hou Bing1ORCID,Tang Changli36ORCID,Liu Fucheng1ORCID,Yang Jie1ORCID,Pan Tao1ORCID,Si Ke1ORCID,Lu Deyun1ORCID,Wang Xiaoxiang1ORCID,Wang Jing1ORCID,Xiong Xing1ORCID,Liu Ji134ORCID,Xie Chunguang2ORCID

Affiliation:

1. Department of Gastroenterology, Integrated Traditional Chinese Medicine and Western Medicine Hospital Affiliated to Chengdu University of Traditional Chinese Medicine/Chengdu First People’s Hospital, Chengdu 610041, China

2. School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China

3. Chengdu Easton Biopharmaceuticals Ltd., Chengdu 611731, China

4. Department of Biochemistry and Molecular Biology, West China School of Basic Medical Science and Forensic Medicine, Sichuan University, Chengdu 610041, China

5. Remeadjohn Technology Co., Ltd., Chengdu 610044, China

6. Pharmacy Department, Xichang People’s Hospital, Xichang 615000, China

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 10μM. HCT116 cells and LS174 cells were employed to investigate the inhibiting effect of (+)-UA (<10μM) on SCF-mediated migration of c-KIT(+) CRC cells. HCT116 cells were employed to investigate the molecular mechanisms. The results indicated that firstly, 8μM (+)-UA decreased ATP content via uncoupling; secondly, 8μM (+)-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, 8μM (+)-UA inhibited SCF-mediated migration of CRC c-KIT(+) cells. Taken together, 8μM could be determined as the effective concentration for (+)-UA to inhibit SCF-mediated migration of CRC c-KIT(+) cells.

Funder

National Natural Science Foundation of China

Publisher

Hindawi Limited

Subject

Complementary and alternative medicine

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