Activation of the Mitochondrial Fragmentation Protein DRP1 Correlates with BRAF V600E Melanoma

Wieder, Shira; Serasinghe, Madhavika N.; Sung, Julie C.; Choi, Daniel; Birgé, Miriam B.; Yao, Jonathan; Bernstein, Emily; Çelebi, Jülide Tok; Chipuk, Jerry E.

doi:10.1038/jid.2015.196

Cited by 54 publications

(66 citation statements)

References 13 publications

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“…Similarly, Mfn2 is downregulated in human gastric tumors [55], while sonic hedgehog signaling induces glycolysis in medulloblastomas in mice by decreasing the expression of Mfn1 and Mfn2 [56]. Conversely, DRP1 levels are upregulated in B-RAF V600E -positive nevi and melanoma, pancreatic, thyroid and breast cancers [55,57,53,58,59]. …”

Section: Oncogenic Signaling and Regulation Of Mitochondrial Dynamicsmentioning

confidence: 99%

“…Given that DRP1 is upregulated in many cancers and is required for oncogenic transformation, indicates that cancer cells may be exquisitely sensitive to DRP1 inhibition. This hypothesis has thus far held true as pharmacological and genetic inhibition of DRP1 decreased the in vitro and in vivo growth of glioblastomas, melanoma, hepatocellular carcinoma, and mesothelioma [57,116,143,144]. …”

Section: Translation Of Mitochondrial Dynamics From the Bench To Bedsidementioning

confidence: 99%

“…However, early work indicates that upregulation of DRP1 may be predictive of breast cancer progression and metastasis [54], while an increased DRP1 Ser616 to Ser637 phosphorylation ratio in lung cancer (meaning increased DRP1 activity) predicts cisplatin resistance and relapse in lung adenocarcinoma patients [146]. Additionally, DRP1 Ser616 phosphorylation status dichotomized wild type B-RAF from B-RAF V600E -positive dysplastic nevi and melanoma [57,53], while another study found DRP1 Ser616 positively correlated with ERK phosphorylation in human pancreatic adenocarcinoma [58], indicating that DRP1 Ser616 status significantly relates to oncogenic MAPK signaling may be useful in determining which lesions may develop into cancer. Finally, DRP1 Ser616 was significantly expressed in BTICs, while evaluation of total DRP1 and DRP1 S616 in normal brain and glioblastoma specimens demonstrated strong positive correlation between DRP1 Ser616 and cancer progression [116].…”

Section: Mitochondrial Dynamics As Biomarkersmentioning

confidence: 99%

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Mitochondrial dynamics as regulators of cancer biology

Trotta

Chipuk

2017

Cell. Mol. Life Sci.

186

163

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Mitochondria are dynamic organelles that supply energy required to drive key cellular processes, such as survival, proliferation, and migration. Critical to all of these processes are changes in mitochondrial architecture, a mechanical mechanism encompassing both fusion and fragmentation (fission) of the mitochondrial network. Changes to mitochondrial shape, size, and localization occur in a regulated manner in order to maintain energy and metabolic homeostasis, while deregulation of mitochondrial dynamics is associated with the onset of metabolic dysfunction and disease. In cancers, oncogenic signals that drive excessive proliferation, increase intracellular stress, and limit nutrient supply are all able to alter the bioenergetic and biosynthetic requirements of cancer cells. Consequently, mitochondrial function and shape rapidly adapt to these hostile conditions in order to support cancer cell proliferation and evade activation of cell death programs. In this review we will discuss the molecular mechanisms governing mitochondrial dynamics and integrate recent insights into how changes in mitochondrial shape affect cellular migration, differentiation, apoptosis, and opportunities for the development of novel targeted cancer therapies.

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Section: Oncogenic Signaling and Regulation Of Mitochondrial Dynamicsmentioning

confidence: 99%

Section: Translation Of Mitochondrial Dynamics From the Bench To Bedsidementioning

confidence: 99%

Section: Mitochondrial Dynamics As Biomarkersmentioning

confidence: 99%

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Mitochondrial dynamics as regulators of cancer biology

Trotta

Chipuk

2017

Cell. Mol. Life Sci.

186

163

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“…Inhibition of BRAF V600E in melanoma cells results in mitochondrial fusion and up-regulation of oxidative phosphorylation genes and increases mitochondrial biogenesis and respiration (13,16). These studies indicate that mitochondrial dynamics, oncogenic MAPK signaling, and cancer metabolism are intricately linked to tumorigenesis (17,18). Moreover, it is becoming evident that melanoma cells are dependent on mitochondria after inhibition of oncogenic MAPK signaling and, therefore, may be vulnerable to compounds that disrupt mitochondrial function.…”

mentioning

confidence: 99%

Disruption of mitochondrial electron transport chain function potentiates the pro-apoptotic effects of MAPK inhibition

Trotta

Gelles

Serasinghe

et al. 2017

Journal of Biological Chemistry

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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 V600E mutation in the kinase v-RAF murine sarcoma viral oncogene homolog B (BRAF), oncogenic signaling enhances glucose-dependent metabolism while reducing mitochondrial ATP production. Likewise, when BRAF is pharmacologically inhibited by targeted therapies ( 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 BRAF 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 G cell cycle arrest. Importantly, although 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 after oncogenic MAPK inhibition.

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“…Indeed, a reduced proliferative rate has been associated with compromised fission machinery and retention of dysfunctional mitochondria in melanoma cell lines (69,73). Also, increased hyper-activation of the fission machinery, which has been positively correlated to the BRAF V600E mutation in human patients, has been implicated in high proliferation of melanoma cells (79).…”

Section: Mitochondria In Melanomamentioning

confidence: 99%

The Complex Role of Autophagy in Melanoma Evolution: New Perspectives From Mouse Models

2020

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Despite tremendous efforts in the last decade to improve treatments, melanoma still represents a major therapeutic challenge and overall survival of patients remains poor. Therefore, identifying new targets to counteract melanoma is needed. In this scenario, autophagy, the "self-eating" process of the cell, has recently arisen as new potential candidate in melanoma. Alongside its role as a recycling mechanism for dysfunctional and damaged cell components, autophagy also clearly sits at a crossroad with metabolism, thereby orchestrating cell proliferation, bioenergetics and metabolic rewiring, all hallmarks of cancer cells. In this regard, autophagy, both in tumor and host, has been flagged as an essential player in melanomagenesis and progression. To pave the way to a better understanding of such a complex interplay, the use of genetically engineered mouse models (GEMMs), as well as syngeneic mouse models, has been undoubtedly crucial. Herein, we will explore the latest discoveries in the field, with particular focus on the potential of these models in unraveling the contribution of autophagy in melanoma, along with the therapeutic advantages that may arise.

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Activation of the Mitochondrial Fragmentation Protein DRP1 Correlates with BRAF V600E Melanoma

Cited by 54 publications

References 13 publications

Mitochondrial dynamics as regulators of cancer biology

Mitochondrial dynamics as regulators of cancer biology

Disruption of mitochondrial electron transport chain function potentiates the pro-apoptotic effects of MAPK inhibition

The Complex Role of Autophagy in Melanoma Evolution: New Perspectives From Mouse Models

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