Disruption of mitochondrial electron transport chain function potentiates the pro-apoptotic effects of MAPK inhibition.
- Andrew P. Trotta1,
- Jesse D. Gelles1,
- Madhavika N. Serasinghe1,
- Patrick Loi1,
- Jack L. Arbiser2 and
- Jerry E. Chipuk1*
- ↵* Corresponding author; email: jerry.chipuk{at}mssm.edu
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Author contributions: A.P.T. and J.E.C. were involved in the conception and design of experiments. A.P.T., P.L., J.D.G., M.N.S. and J.E.C. were involved in data acquisition, analysis, and interpretation. A.P.T. and J.E.C. prepared figures and wrote the manuscript. All authors were involved in critically reviewed the results and approved the final version of the manuscript.
Abstract
The mitochondrial network is a major site of ATP production through the coupled integration of the electron transport chain (ETC) with oxidative phosphorylation. In melanoma, arising from the Val600Glu mutation in the kinase v-RAF murine sarcoma viral oncogene homolog B (BRAFV600E), oncogenic signaling enhances glucose-dependent metabolism, while reducing mitochondrial ATP production. Likewise, when BRAFV600E is pharmacologically inhibited by targeted therapies (e.g. PLX-4032/Vemurafenib), glucose metabolism is reduced and cells increase mitochondrial ATP production to sustain survival. Therefore, collateral inhibition of oncogenic signaling and mitochondrial respiration may help enhance the therapeutic benefit of targeted therapies. Honokiol (HKL) is a well-tolerated small molecule that disrupts mitochondrial function; however its underlying mechanisms and potential utility with targeted anticancer therapies remain unknown. Using wild-type BRAF and BRAFV600E melanoma model systems, we demonstrate here that HKL administration rapidly reduces mitochondrial respiration by broadly inhibiting ETC complexes I, II, and V, resulting in decreased ATP levels. The subsequent energetic crisis induced two cellular responses involving cyclin-dependent kinases (CDKs). First, loss of CDK1-mediated phosphorylation of the mitochondrial division GTPase dynamin-related protein 1 promoted mitochondrial fusion, thus coupling mitochondrial energetic status and morphology. Second, HKL decreased CDK2 activity, leading to G1 cell cycle arrest. Importantly, while pharmacological inhibition of oncogenic MAPK signaling increased ETC activity, co-treatment with HKL ablated this response and vastly enhanced the rate of apoptosis. Collectively, these findings integrate HKL action with mitochondrial respiration and shape and substantiate a pro-survival role of mitochondrial function in melanoma cells following oncogenic MAPK inhibition.
- apoptosis
- mitochondria
- mitochondrial respiratory chain complex
- oncogene
- respiration
- mitochondrial dynamics
- targeted therapy
- Received March 14, 2017.
- Accepted May 25, 2017.
- Copyright © 2017, The American Society for Biochemistry and Molecular Biology
