TitleMitochondrial complex I inhibitor deguelin induces metabolic reprogramming and sensitizes vemurafenib-resistant BRAF mutation bearing metastatic melanoma cells.
Publication TypeJournal Article
Year of Publication2019
AuthorsCarpenter EL, Chagani S, Nelson D, Cassidy PB, Laws M, Ganguli-Indra G, Indra AK
JournalMol Carcinog
Date Published2019 Jun 18
ISSN1098-2744
Abstract

Treatment with vemurafenib, a potent and selective inhibitor of mitogen-activated protein kinase signaling downstream of the BRAF oncogene, elicits dramatic clinical responses in patients with metastatic melanoma. Unfortunately, the clinical utility of this drug is limited by a high incidence of drug resistance. Thus, there is an unmet need for alternative therapeutic strategies to treat vemurafenib-resistant metastatic melanomas. We have conducted high-throughput screening of two bioactive compound libraries (Siga and Spectrum libraries) against a metastatic melanoma cell line (A2058) and identified two structurally analogous compounds, deguelin and rotenone, from a cell viability assay. Vemurafenib-resistant melanoma cell lines, A2058R and A375R (containing the BRAF mutation), also showed reduced proliferation when treated with these two compounds. Deguelin, a mitochondrial complex I inhibitor, was noted to significantly inhibit oxygen consumption in cellular metabolism assays. Mechanistically, deguelin treatment rapidly activates AMPK signaling, which results in inhibition of mTORC1 signaling and differential phosphorylation of mTORC1's downstream effectors, 4E-BP1 and p70S6 kinase. Deguelin also significantly inhibited ERK activation and Ki67 expression without altering Akt activation in the same timeframe in the vemurafenib-resistant melanoma cells. These data posit that treatment with metabolic regulators, such as deguelin, can lead to energy starvation, thereby modulating the intracellular metabolic environment and reducing survival of drug-resistant melanomas harboring BRAF mutations.

DOI10.1002/mc.23068
Alternate JournalMol. Carcinog.
PubMed ID31211467
Grant List1R01ES016629-01A1 (PI: AI) / / National Institute of Environmental Health Sciences /
T32CA106195 / / National Cancer Institute of the National Institutes of Health /
/ / OSU College of Pharmacy Pilot Project for highthroughput screen /