Protective autophagy is involved in resistance towards MET inhibitors in human gastric adenocarcinoma cells

Humbert, Magali; Medova, Michaela; Aebersold, Daniel; Blaukat, Andree; Bladt, Friedhelm; Fey, Martin; Zimmer, Yitzhak; Tschan, Mario P. (2013). Protective autophagy is involved in resistance towards MET inhibitors in human gastric adenocarcinoma cells. Biochemical and biophysical research communications, 431(2), pp. 264-269. Academic Press 10.1016/j.bbrc.2012.12.120

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MET, also known as hepatocyte growth factor receptor (HGFR), is a receptor tyrosine kinase with an important role, both in normal cellular function as well as in oncogenesis. In many cancer types, abnormal activation of MET is related to poor prognosis and various strategies to inhibit its function, including small molecule inhibitors, are currently in preclinical and clinical evaluation. Autophagy, a self-digesting recycling mechanism with cytoprotective functions, is induced by cellular stress. This process is also induced upon cytotoxic drug treatment of cancer cells and partially allows these cells to escape cell death. Thus, since autophagy protects different tumor cells from chemotherapy-induced cell death, current clinical trials aim at combining autophagy inhibitors with different cancer treatments. We found that in a gastric adenocarcinoma cell line GTL-16, where MET activity is deregulated due to receptor overexpression, two different MET inhibitors PHA665752 and EMD1214063 lead to cell death paralleled by the induction of autophagy. A combined treatment of MET inhibitors together with the autophagy inhibitor 3-MA or genetically impairing autophagy by knocking down the key autophagy gene ATG7 further decreased cell viability of gastric cancer cells. In general, we observed the induction of cytoprotective autophagy in MET expressing cells upon MET inhibition and a combination of MET and autophagy inhibition resulted in significantly decreased cell viability in gastric cancer cells.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology

UniBE Contributor:

Humbert, Magali; Medova, Michaela; Aebersold, Daniel; Fey, Martin; Zimmer, Yitzhak and Tschan, Mario

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0006-291X

Publisher:

Academic Press

Language:

English

Submitter:

Beatrice Scheidegger

Date Deposited:

03 Apr 2014 15:55

Last Modified:

03 Apr 2014 15:55

Publisher DOI:

10.1016/j.bbrc.2012.12.120

PubMed ID:

23313490

Uncontrolled Keywords:

MET, Autophagy, ATG7, MET inhibitors, c-Met

URI:

https://boris.unibe.ch/id/eprint/42557

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