TY - JOUR
T1 - Mitochondrial complex I inhibitor deguelin induces metabolic reprogramming and sensitizes vemurafenib-resistant BRAFV600E mutation bearing metastatic melanoma cells
AU - Carpenter, Evan L.
AU - Chagani, Sharmeen
AU - Nelson, Dylan
AU - Cassidy, Pamela B.
AU - Laws, Madeleine
AU - Ganguli-Indra, Gitali
AU - Indra, Arup K.
N1 - Funding Information:
We thank members of the Indra lab and the OSU College of Pharmacy for their continuous support and encouragement. We also thank Dr. Siva Kolluri at OSU for providing the materials for the apoptosis immunoblots. The research reported in this publication was supported in part by National Institute of Environmental Health Sciences (NIEHS) of the National Institutes of Health (NIH) under the award number 1R01ES016629-01A1 (PI: AI), National Cancer Institute of the NIH under award number T32CA106195 and the OSU/OHSU College of Pharmacy Pilot Project Grant to AI. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Funding Information:
We thank members of the Indra lab and the OSU College of Pharmacy for their continuous support and encouragement. We also thank Dr. Siva Kolluri at OSU for providing the materials for the apoptosis immunoblots. The research reported in this publication was supported in part by National Institute of Environmental Health Sciences (NIEHS) of the National Institutes of Health (NIH) under the award number 1R01ES016629‐01A1 (PI: AI), National Cancer Institute of the NIH under award number T32CA106195 and the OSU/OHSU College of Pharmacy Pilot Project Grant to AI.
Publisher Copyright:
© 2019 Wiley Periodicals, Inc.
PY - 2019/9
Y1 - 2019/9
N2 - 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.
AB - 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.
KW - BRAFV600E
KW - metabolic reprogramming
KW - metastatic melanoma
KW - vemurafenib resistance
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U2 - 10.1002/mc.23068
DO - 10.1002/mc.23068
M3 - Article
C2 - 31211467
AN - SCOPUS:85070934004
VL - 58
SP - 1680
EP - 1690
JO - Molecular Carcinogenesis
JF - Molecular Carcinogenesis
SN - 0899-1987
IS - 9
ER -