MFN2 suppresses cancer progression through inhibition of mTORC2/Akt signaling

Xu, Kecheng; Guo, Chen; Li, Xiaobo; Wu, Xiaoqin; Chen, Zhijie; Xu, Jianhua; Zhu, Yu; Yin, Peihao; Liang, Xin; Dong, Lei

doi:10.1038/srep41718

Cited by 96 publications

(96 citation statements)

References 35 publications

(34 reference statements)

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“…Akt plays a major role in regulating ER and mitochondrial apoptosis pathways. 24,25) In this study, phosphor-Akt was significantly increased by bavachin in a time-dependent manner, while total Akt have no apparent change (Figs. 5A, B).…”

Section: Effect Of Bavachin On Viability In Hepg2 Cellsmentioning

confidence: 90%

“…[54][55][56] A recent study suggested that the overexpression of Mfn2 suppressed cancer progression through inhibition of Akt signaling. 24) Furthermore, bavachin was reported to exhibit direct effect on Akt phosphorylation. 11,57) In this study, we showed that Mfn2 ablation by the siRNA resulted in the inhibition of phosphor-Akt, and inhibition of phosphorAkt also aggravated bavachin-induced ER stress (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells

Yang

Tang²,

Hao³

et al. 2018

Biological & Pharmaceutical Bulletin

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As a traditional herbal medicine, the fruits of Psoralea corylifolia L. (Fructus Psoraleae (FP)) have been widely used for the treatment of various skin diseases for hundred years. Recently, the emerging FPinduced toxic effects, especially hepatotoxicity, in clinic are getting the public's attention. However, its exact toxic components and mechanisms underlying remain unclear. Bavachin, one of flavonoids in FP, has been documented as a hepatotoxic substance, and the present study aimed to determine the toxicity caused by bavachin and the possible toxic mechanisms involved using human hepatocellular carcinoma (HepG2) cells. Our results showed that bavachin could significantly inhibited cell proliferation and trigger the endoplasmic reticulum (ER) stress in a dose dependent manner. Downregulating ER stress using tauroursodeoxycholic acid (TUDCA) obvious attenuated bavachin-triggerd cell apoptosis. Then, small interfering RNA (siRNA) knock-down of Mitofusion2 (Mfn2) resulted in a remarkable aggravation of ER stress through the inhibition of the phosphorylation of protein kinase B (Akt). Additionally, suppression of reactive oxygen species (ROS) by ROS Scavenger (N-acetyl-l-cystein (NAC)) also reduced bavachin-induced ER stress. Taken together, our study demonstrated that bavachin-induced ER stress caused cell apoptosis by Mfn2-Akt pathway, and that ROS may participate upstream in this mechanism. Here, we not only provide a new understanding of ROS/ Mfn2/Akt pathway in bavachin-induced cytotoxicity via the ER stress, but also identify a new specific intervention to prevent FP-induced hepatotoxicity in the future.

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Section: Effect Of Bavachin On Viability In Hepg2 Cellsmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells

Yang

Tang²,

Hao³

et al. 2018

Biological & Pharmaceutical Bulletin

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“…Proteins involved in regulation of mitochondrial dynamics are now identified as important biomarkers of malignancy, including therapeutic targets in several tumor types (21). Thus, the enhancement of mitochondrial fragmentation by attenuating MFN2 has been associated with increased genomic instability and reduced migration and invasion in breast cancer cell lines, which predominantly exhibit fused mitochondrial morphology (47,48). Impaired mitochondrial fusion also causes aberrant mitochondrial function, characterized by acquired mitochondrial DNA mutations and ROS production (36).…”

Section: Discussionmentioning

confidence: 99%

Cystathionine β‐synthase regulates mitochondrial morphogenesis in ovarian cancer

et al. 2018

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Deregulation of mitochondrial morphogenesis, a dynamic equilibrium between mitochondrial fusion and fission processes, is now evolving as a key metabolic event that fuels tumor growth and therapy resistance. However, fundamental knowledge underpinning how cancer cells reprogram mitochondrial morphogenesis remains incomplete. Here, we report that cystathionine β-synthase (CBS) reprograms mitochondrial morphogenesis in ovarian cancer (OvCa) cells by selectively regulating the stability of mitofusin 2 (MFN2). Clinically, high expression of both CBS and MFN2 implicates poor overall survival of OvCa patients, and a significant association between CBS and MFN2 expression exists in individual patients in the same data set. The silencing of CBS by small interfering RNA or inhibition of its catalytic activity by a small molecule inhibitor creates oxidative stress that activates JNK. Activated JNK phosphorylates MFN2 to recruit homologous to the E6-AP carboxyl terminus' domain-containing ubiquitin E3 ligase for its degradation via the ubiquitin-proteasome system. Supplementation with hydrogen sulfide or glutathione (the catalytic products of CBS enzymatic activity), anti-oxidants, or a JNK inhibitor restores MFN2 expression. In CBS-silenced orthotopic xenograft tumor tissues, MFN2 but not MFN1 is selectively downregulated. In summary, this report reveals a role for deregulated mitochondrial morphogenesis in OvCa, suggests one of the mechanisms for this deregulation, and provides a way to correct it through modulation of the metabolic enzyme CBS.-Chakraborty, P. K., Murphy, B., Mustafi, S. B., Dey, A., Xiong, X., Rao, G., Naz, S., Zhang, M., Yang, D., Dhanasekaran, D. N., Bhattacharya, R., Mukherjee, P. Cystathionine β-synthase regulates mitochondrial morphogenesis in ovarian cancer.

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“…As for cell growth, mitochondrial fusion seems to oppose fission and inhibits invasiveness of both breast and lung cancers (Xu et al, 2017). Low expression of MFN2 for patients of both diseases correlates with poor prognosis.…”

Section: Cancer Cell Migrationmentioning

confidence: 99%

Mitochondrial Dynamics in Regulating the Unique Phenotypes of Cancer and Stem Cells

2017

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Cancer and stem cells appear to share a common metabolic profile that is characterized by high utilization of glucose through aerobic glycolysis. In the presence of sufficient nutrients, this metabolic strategy provides sufficient cellular ATP while additionally providing important metabolites necessary for the biosynthetic demands of continuous cell proliferation. Recent studies indicate that this metabolic profile is dependent on genes that regulate the fusion and fission of mitochondria. High levels of mitochondrial fission activity are associated with high proliferation and invasiveness in some cancer cells and with self-renewal and resistance to differentiation in some stem cells. These observations reveal new ways in which mitochondria regulate cell physiology, through their effects on metabolism and cell signaling.

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MFN2 suppresses cancer progression through inhibition of mTORC2/Akt signaling

Cited by 96 publications

References 35 publications

Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells

Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells

Cystathionine β‐synthase regulates mitochondrial morphogenesis in ovarian cancer

Mitochondrial Dynamics in Regulating the Unique Phenotypes of Cancer and Stem Cells

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