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Dual suppression of inner and outer mitochondrial membrane functions augments apoptotic responses to oncogenic MAPK inhibition.

ABSTRACT: Mitogen-activated protein kinase (MAPK) pathway inhibitors show promise in treating melanoma, but are unsuccessful in achieving long-term remission. Concordant with clinical data, BRAFV600E melanoma cells eliminate glycolysis upon inhibition of BRAFV600E or MEK with the targeted therapies Vemurafenib or Trametinib, respectively. Consequently, exposure to these therapies reprograms cellular metabolism to increase mitochondrial respiration and restrain cell death commitment. As the inner mitochondrial membrane (IMM) is sub-organellar site of oxidative phosphorylation (OXPHOS), and the outer mitochondrial membrane (OMM) is the major site of anti-apoptotic BCL-2 protein function, we hypothesized that suppressing these critical mitochondrial membrane functions would be a rational approach to maximize the pro-apoptotic effect of MAPK inhibition. Here, we demonstrate that disruption of OXPHOS with the mitochondria-specific protonophore BAM15 promotes the mitochondrial pathway of apoptosis only when oncogenic MAPK signaling is inhibited. Based on RNA-sequencing analyses of nevi and primary melanoma samples, increased pro-apoptotic BCL-2 family expression positively correlates with high-risk disease suggesting a highly active anti-apoptotic BCL-2 protein repertoire likely contributes to worse outcome. Indeed, combined inhibition of the anti-apoptotic BCL-2 repertoire with BH3-mimetics, OXPHOS, and oncogenic MAPK signaling induces fulminant apoptosis and eliminates clonogenic survival. Altogether, these data suggest that dual suppression of IMM and OMM functions may unleash the normally inadequate pro-apoptotic effects of oncogenic MAPK inhibition to eradicate cancer cells, thus preventing the development of resistant disease, and ultimately, supporting long-term remission.

SUBMITTER: Serasinghe MN

PROVIDER: S-EPMC5833689 | biostudies-other | 2018 Jan

REPOSITORIES: biostudies-other

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Dual suppression of inner and outer mitochondrial membrane functions augments apoptotic responses to oncogenic MAPK inhibition.

Serasinghe Madhavika N MN Gelles Jesse D JD Li Kent K Zhao Lauren L Abbate Franco F Syku Marie M Mohammed Jarvier N JN Badal Brateil B Rangel Cuahutlehuanitzin A CA Hoehn Kyle L KL Celebi Julide Tok JT Chipuk Jerry Edward JE

Cell death & disease 20180118 2

Mitogen-activated protein kinase (MAPK) pathway inhibitors show promise in treating melanoma, but are unsuccessful in achieving long-term remission. Concordant with clinical data, BRAF<sup>V600E</sup> melanoma cells eliminate glycolysis upon inhibition of BRAF<sup>V600E</sup> or MEK with the targeted therapies Vemurafenib or Trametinib, respectively. Consequently, exposure to these therapies reprograms cellular metabolism to increase mitochondrial respiration and restrain cell death commitment. ...[more]

PMID: 29348439

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Project description:BackgroundBridging factors are relational ties, formal arrangements, and processes that connect outer system and inner organizational contexts. They may be critical drivers of evidence-based practice (EBP) implementation and sustainment. Yet, the complex interplay between outer and inner contexts is often not considered. Bridging factors were recently defined in the updated Exploration, Preparation, Implementation, Sustainment (EPIS) framework. Further identification and specification of this construct will advance implementation models, measures, and methods. Our goal is to advance bridging factor research by identifying relevant dimensions and exemplifying these dimensions through illustrative case studies.MethodsWe used a multiple case study design. Each case (n = 10) represented different contexts, EBPs, and bridging factor types. Inclusion criteria were the presence of clearly distinguishable outer and inner contexts, identifiable bridging factor, sufficient information to describe how the bridging factor affected implementation, and variation from other cases. We used an iterative qualitative inquiry process to develop and refine a list of dimensions. Case data were entered into a matrix. Dimensions comprised the rows and case details comprised the columns. After a review of all cases, we collectively considered and independently coded each dimension as function or form.ResultsWe drew upon the concepts of functions and forms, a distinction originally proposed in the complex health intervention literature. Function dimensions help define the bridging factor and illustrate its purpose as it relates to EBP implementation. Form dimensions describe the specific structures and activities that illustrate why and how the bridging factor has been customized to a local implementation experience. Function dimensions can help researchers and practitioners identify the presence and purpose of bridging factors, whereas form dimensions can help us understand how the bridging factor may be designed or modified to support EBP implementation in a specific context. We propose five function and three form bridging factor dimensions.ConclusionsBridging factors are described in many implementation models and studies, but without explicit reference or investigation. Bridging factors are an understudied and critical construct that requires further attention to facilitate implementation research and practice. We present specific recommendations for a bridging factors research agenda.

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Dual suppression of inner and outer mitochondrial membrane functions augments apoptotic responses to oncogenic MAPK inhibition.

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Dual suppression of inner and outer mitochondrial membrane functions augments apoptotic responses to oncogenic MAPK inhibition.

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