Mitochondrial complex I inhibitor deguelin induces metabolic reprogramming and sensitizes vemurafenib-resistant BRAFV600E mutation bearing metastatic melanoma cells

Evan L. Carpenter, Sharmeen Chagani, Dylan Nelson, Pamela Cassidy, Madeleine Laws, Gitali Ganguli-Indra, Arup K. Indra

Research output: Contribution to journalArticle

Abstract

Treatment with vemurafenib, a potent and selective inhibitor of mitogen-activated protein kinase signaling downstream of the BRAFV600E 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 BRAFV600E 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.

Original languageEnglish (US)
Pages (from-to)1680-1690
Number of pages11
JournalMolecular Carcinogenesis
Volume58
Issue number9
DOIs
StatePublished - Jan 1 2019

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Melanoma
Mutation
Libraries
Rotenone
Cell Line
AMP-Activated Protein Kinases
Therapeutics
Starvation
Mitogen-Activated Protein Kinases
Oncogenes
Drug Resistance
Oxygen Consumption
Pharmaceutical Preparations
PLX4032
deguelin
Cell Survival
Phosphotransferases
Phosphorylation
Survival
Incidence

Keywords

  • BRAFV600E
  • metabolic reprogramming
  • metastatic melanoma
  • vemurafenib resistance

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Mitochondrial complex I inhibitor deguelin induces metabolic reprogramming and sensitizes vemurafenib-resistant BRAFV600E mutation bearing metastatic melanoma cells. / Carpenter, Evan L.; Chagani, Sharmeen; Nelson, Dylan; Cassidy, Pamela; Laws, Madeleine; Ganguli-Indra, Gitali; Indra, Arup K.

In: Molecular Carcinogenesis, Vol. 58, No. 9, 01.01.2019, p. 1680-1690.

Research output: Contribution to journalArticle

Carpenter, Evan L. ; Chagani, Sharmeen ; Nelson, Dylan ; Cassidy, Pamela ; Laws, Madeleine ; Ganguli-Indra, Gitali ; Indra, Arup K. / Mitochondrial complex I inhibitor deguelin induces metabolic reprogramming and sensitizes vemurafenib-resistant BRAFV600E mutation bearing metastatic melanoma cells. In: Molecular Carcinogenesis. 2019 ; Vol. 58, No. 9. pp. 1680-1690.
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