Mitochondrial complex I inhibitor deguelin induces metabolic reprogramming and sensitizes vemurafenib‐resistant BRAFV600E mutation bearing metastatic melanoma cells. Issue 9 (18th June 2019)

• Record Type: Journal Article
• Authors: Carpenter, Evan L.; Chagani, Sharmeen; Nelson, Dylan; Cassidy, Pamela B.; Laws, Madeleine; Ganguli‐Indra, Gitali; Indra, Arup K.
• Is Part Of: Molecular carcinogenesis. Volume 58:Issue 9(2019)
• Page Start: 1680
• Page End: 1690
• Publication Date: 2019-06-18
• Subjects: BRAFV600E -- metabolic reprogramming -- metastatic melanoma -- vemurafenib resistance; Carcinogenesis -- Molecular aspects -- Periodicals; 616.994071
• DOI: 10.1002/mc.23068
• Languages: English
• ISSNs: 0899-1987

Abstract

Abstract: Treatment with vemurafenib, a potent and selective inhibitor of mitogen‐activated protein kinase signaling downstream of the BRAF V600E 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 V600E 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 V600E mutations.