Mcl-1 involvement in mitochondrial dynamics is associated with apoptotic cell death

Morciano, Giampaolo; Giorgi, Carlotta; Balestra, Dario; Marchi, Saverio; Perrone, Daniela; Pinotti, Mirko; Pinton, Paolo

doi:10.1091/mbc.e15-01-0028

Cited by 111 publications

(87 citation statements)

References 74 publications

(82 reference statements)

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“…Fusion also reportedly spares mitochondria from autophagy activated under nutrient starvation [6,26]. MFN2-dependent tethering of mitochondria to the ER increases upon fusion, enhancing lipid and calcium transfer between organelles [27], but simultaneously increases sensitivity to calcium-dependent apoptosis [28,29]. Fission in turn is critical for mitophagy by generating one depolarized and one hyperpolarized mitochondrion.…”

Section: Mitochondrial Dynamics Mitochondrial Quality Control and Cementioning

confidence: 99%

“…Similar to the interplay of Bcl-2 family proteins and Parkin, alterations in mitochondrial dynamics also mediate calcium-dependent apoptosis, which is enhanced in highly interconnected mitochondria [28,29]. In this context, Mcl-1S, a Mcl-1 splice variant that displays proapoptotic activity, facilitates Ca 2+ -dependent apoptosis by interfering with Drp1 recruitment to mitochondria, allowing unopposed fusion [28].…”

Section: Mitochondrial Dynamics Mitochondrial Quality Control and Cementioning

confidence: 99%

“…In this context, Mcl-1S, a Mcl-1 splice variant that displays proapoptotic activity, facilitates Ca 2+ -dependent apoptosis by interfering with Drp1 recruitment to mitochondria, allowing unopposed fusion [28]. Thus, distinct pathways merge on the mitochondrial dynamics machinery to modulate network architecture, which either restores homeostasis, or, depending on the type and degree of damage, execute cell death.…”

Section: Mitochondrial Dynamics Mitochondrial Quality Control and Cementioning

confidence: 99%

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Regulators of mitochondrial dynamics in cancer

Senft

Ronai

2016

Current Opinion in Cell Biology

204

214

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Mitochondrial dynamics encompasses processes associated with mitochondrial fission and fusion, affecting their number, degree of biogenesis, and the induction of mitophagy. These activities determine the balance between mitochondrial energy production and cell death programs. Processes governing mitochondrial dynamics are tightly controlled in physiological conditions and are often deregulated in cancer. Mitochondrial protein homeostasis, transcriptional regulation, and post-translational modification are among processes that govern the control of mitochondrial dynamics. Cancer cells alter mitochondrial dynamics to resist apoptosis and adjust their bioenergetic and biosynthetic needs to support tumor initiating and transformation properties including proliferation, migration, and therapeutic resistance. This review focuses on key regulators of mitochondrial dynamics and their role in cancer.

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Section: Mitochondrial Dynamics Mitochondrial Quality Control and Cementioning

confidence: 99%

Section: Mitochondrial Dynamics Mitochondrial Quality Control and Cementioning

confidence: 99%

Section: Mitochondrial Dynamics Mitochondrial Quality Control and Cementioning

confidence: 99%

See 1 more Smart Citation

Regulators of mitochondrial dynamics in cancer

Senft

Ronai

2016

Current Opinion in Cell Biology

204

214

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“…C-FLIP disrupts initiation of extrinsic apoptotic pathway through inhibition of Caspase-8 activation (21). The intrinsic apoptosis pathway is characterized by loss of mitochondrial membrane potential and release of cytochrome c. Mcl-1 inhibits the intrinsic apoptosis pathway by preventing loss of mitochondrial membrane potential and the release of cytochrome c (24,25). A previous study indicated that sorafenib enhances vorinostat-induced extrinsic and intrinsic apoptotic pathways via inhibiting expression of NF-κB-modulated anti-apoptotic proteins in HCC Huh7 cells in vitro and in vivo (4).…”

Section: Discussionmentioning

confidence: 99%

Amentoflavone enhances sorafenib-induced apoptosis through extrinsic and intrinsic pathways in sorafenib-resistant hepatocellular carcinoma SK-Hep1 cells in vitro

et al. 2017

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Abstract. The present study aimed to evaluate the effects of amentof lavone on sorafenib-induced apoptosis in sorafenib-resistant hepatocellular carcinoma (HCC) cells. The sorafenib-resistant SK-Hep1 (SK-Hep1R) cell line was established for the present study. Initially, the differences in sorafenib-induced cytotoxicity and apoptosis between wild-type SK-Hep1 and SK-Hep1R cells were verified using the MTT assay and flow cytometry. The effects of amentoflavone on sorafenib-induced cytotoxicity and apoptosis were then investigated using MTT, flow cytometry, DNA gel electrophoresis and western blot analysis. The results demonstrated that cell viability of SK-Hep1R cells was increased compared with that of SK-Hep1 cells following treatment with different concentrations of sorafenib for 24 h. Apoptosis of SK-Hep1R cells was lower than that of SK-Hep1 cells following treatment with 20 µM sorafenib for 24 h. Amentoflavone alone did not inhibit cell viability but significantly triggered sorafenib-induced cytotoxicity and apoptosis in SK-Hep1R cells. Amentoflavone not only reversed sorafenib-induced anti-apoptotic protein levels but also enhanced sorafenib-induced pro-apoptotic protein expression in SK-Hep1R cells. In conclusion, amentoflavone may be used as a sorafenib sensitizer to enhance sorafenib-induced cytotoxicity and trigger sorafenib-induced apoptosis through extrinsic and intrinsic pathways in SK-Hep1R cells. IntroductionSorafenib, a multi-kinase inhibitor, has been approved by the US Food and Drug Administration to improve overall survival and time to progression of patients with advanced hepatocellular carcinoma (HCC) (1). Sorafenib induces apoptosis and inhibits angiogenesis in HCC through blockage of the rapidly accelerated fibrosarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase cascade, vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinase signaling (2,3). Sorafenib has also been demonstrated to enhance the therapeutic efficacy of anticancer agents and radiotherapy via inhibition of nuclear factor-κB (NF-κB) or signal transducer and activator of transcription 3 (STAT3)-modulated resistance to anticancer treatments in HCC models in vitro and in vivo (4,5). However, long-term exposure to sorafenib for HCC cells induces sorafenib resistance and results in tumor progression (6,7). Therefore, development of sorafenib sensitizers, which reverse sorafenib resistance and results in sorafenib-inhibited tumor progression in sorafenib-resistant HCC cells, is important. Amentoflavone enhances sorafenib-induced apoptosis through extrinsic and intrinsic pathways in sorafenib-resistant hepatocellular carcinoma SK-Hep1 cells in vitro

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“…Proteolytically cleaved amino-truncated MCL-1 can localise to the inner mitochondrial membrane and is important for mitochondrial structure and physiology. 48,49 Furthermore, cell cycle progression by MCL-1 is also mediated through the direct recruitment and inhibition of CDK1, due a reduced capacity of CDK1 to bind to Cyclin 1B. 50 In this manner MCL-1 binding may subvert the interaction of other target proteins thereby restricting kinase activity eg by binding to CDK1 and preventing cell cycle progression.…”

Section: Mcl-1 Is Not Just a Mediator Of Cell Survivalmentioning

confidence: 99%

Myeloid cell leukemia 1 (MCL-1), an unexpected modulator of protein kinase signaling during invasion

Young

Timpson

Gallego‐Ortega

et al. 2017

Cell Adhesion & Migration

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Myeloid cell leukemia-1 (MCL-1), closely related to B-cell lymphoma 2 (BCL-2), has a well-established role in cell survival and has emerged as an important target for cancer therapeutics. We have demonstrated that inhibiting MCL-1 is efficacious in suppressing tumour progression in pre-clinical models of breast cancer and revealed that in addition to its role in cell survival, MCL-1 modulated cellular invasion. Utilizing a MCL-1-specific genetic antagonist, we found two possible mechanisms; firstly MCL-1 directly binds to and alters the phosphorylation of the cytoskeletal remodeling protein, Cofilin, a protein important for cytoskeletal remodeling during invasion, and secondly MCL-1 modulates the levels SRC family kinases (SFKs) and their targets. These data provide evidence that MCL-1 activities are not limited to endpoints of extracellular and intracellular signaling culminating in cell survival as previously thought, but can directly modulate the output of SRC family kinases signaling during cellular invasion. Here we review the pleotropic roles of MCL-1 and discuss the implications of this newly discovered effect on protein kinase signaling for the development of cancer therapeutics.

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Mcl-1 involvement in mitochondrial dynamics is associated with apoptotic cell death

Cited by 111 publications

References 74 publications

Regulators of mitochondrial dynamics in cancer

Regulators of mitochondrial dynamics in cancer

Amentoflavone enhances sorafenib-induced apoptosis through extrinsic and intrinsic pathways in sorafenib-resistant hepatocellular carcinoma SK-Hep1 cells in vitro

Myeloid cell leukemia 1 (MCL-1), an unexpected modulator of protein kinase signaling during invasion

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