Mitochondrial Reprogramming Regulates Breast Cancer Progression

Kannan, Anbarasu; Wells, Robert B.; Sivakumar, Subramaniam; Komatsu, Setsuko; Singh, Karan P.; Samten, Buka; Philley, Julie V.; Sauter, Edward R.; Ikebe, Mitsuo; Idell, Steven; Gupta, Sudeep; Dasgupta, Santanu

doi:10.1158/1078-0432.ccr-15-2456

Cited by 44 publications

(62 citation statements)

References 44 publications

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“…This was accompanied by decreased lung and liver metastases and primary tumor growth (49). SH3GL2 depletion reversed this phenotype (49). This indicates that the anti-tumor functions of Mfn2 are also mitochondrial-dependent.…”

Section: Discussionmentioning

confidence: 92%

“…Although the absence of the p21 Ras motif or the PKA phosphorylation site at Ser442 of Mfn2 has no effect on its mitochondrial membrane localization (3), altered mitochondrial function in breast cancer has been observed (49). In breast cancer cells, with the overexpression of Mfn2, the vesicular endocytosis-associated protein, SH3 domain-containing GRB2-like protein 2 (SH3GL2), was demonstrated to translocate to mitochondria, and induce the production of superoxide and the release of cytochrome C from the mitochondria to the cytoplasm (49).…”

Section: Discussionmentioning

confidence: 99%

“…In breast cancer cells, with the overexpression of Mfn2, the vesicular endocytosis-associated protein, SH3 domain-containing GRB2-like protein 2 (SH3GL2), was demonstrated to translocate to mitochondria, and induce the production of superoxide and the release of cytochrome C from the mitochondria to the cytoplasm (49). This was accompanied by decreased lung and liver metastases and primary tumor growth (49).…”

Section: Discussionmentioning

confidence: 99%

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The anti-tumor effects of Mfn2 in breast cancer are dependent on promoter DNA methylation, the P21Ras motif and PKA phosphorylation site

Dong

Shan

et al. 2018

Oncol Lett

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Abstract. Mitofusin 2 (Mfn2) is expressed in numerous human tissues and serves a pivotal role in cell proliferation. However, Mfn2 is considered as an anti-tumor gene, and is silenced in human malignant tumors, including those of breast cancer. However, the mechanisms contributing to Mfn2 silencing and the mechanism of its anti-tumor function in breast cancer remain unclear. In the present study, hypoexpression of Mfn2, and hypermethylation of its promoter, was confirmed in human breast cancer cells and in breast cancer tissues by reverse transcription-quantitative polymerase chain reaction (PCR) and methylation specific PCR, respectively. Chemical demethylation treatment with 5-aza-2'-deoxycytidine upregulated the mRNA expression level of Mfn2 in MCF-7 cells in a dose-dependent manner. In addition, overexpression of Mfn2 repressed the proliferation, migration and invasion of MCF-7 cells, mediated by inhibition of the Ras-extracellular signal-regulated kinase (ERK)1/2 signaling pathway. However, overexpression of Mfn2 with deletion of the p21Ras motif (Mfn2 ΔRas ) and protein kinase A (PKA) phosphorylation site (Mfn2 ΔPKA ) partially reduced the anti-tumor function of Mfn2, and inhibited the Ras-ERK1/2 signaling pathway. Taken together, the present study confirmed the anti-tumor effects of Mfn2 in human breast cancer and clarified that the mechanism of its anti-tumor functions includes promoter DNA methylation, the P21 Ras binding site and PKA phosphorylation.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The anti-tumor effects of Mfn2 in breast cancer are dependent on promoter DNA methylation, the P21Ras motif and PKA phosphorylation site

Dong

Shan

et al. 2018

Oncol Lett

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“…5a,b arrowheads). We observed an EMT phenotype (arrowheads) as determined by cell morphology3132 accompanied by an increased invasion (p = 0.0001) of both the cell lines following the exosomes treatment (Fig. 5a,b).…”

Section: Resultsmentioning

confidence: 80%

Genetic Mutation and Exosome Signature of Human Papilloma Virus Associated Oropharyngeal Cancer

Kannan

Hertweck

Philley

et al. 2017

Sci Rep

Self Cite

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Human papilloma virus-16 (HPV-16) associated oropharyngeal cancer (HPVOPC) is increasing alarmingly in the United States. We performed whole genome sequencing of a 44 year old, male HPVOPC subject diagnosed with moderately differentiated tonsillar carcinoma. We identified new somatic mutation in MUC16 (A.k.a. CA-125), MUC12, MUC4, MUC6, MUC2, SIRPA, HLA-DRB1, HLA-A and HLA-B molecules. Increased protein expression of MUC16, SIRPA and decreased expression of HLA-DRB1 was further demonstrated in this HPVOPC subject and an additional set of 15 HPVOPC cases. Copy number gain (3 copies) was also observed for MUC2, MUC4, MUC6 and SIRPA. Enhanced expression of MUC16, SIRPA and HPV-16-E7 protein was detectable in the circulating exosomes of numerous HPVOPC subjects. Treatment of non-tumorigenic mammary epithelial cells with exosomes derived from aggressive HPVOPC cells harboring MUC16, SIRPA and HPV-16-E7 proteins augmented invasion and induced epithelial to mesenchymal transition (EMT) accompanied by an increased expression ratio of the EMT markers Vimentin/E-cadherin. Exosome based screening of key HPVOPC associated molecules could be beneficial for early cancer diagnosis, monitoring and surveillance.

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“…Recently, the pro-apoptotic and anti-proliferative effects of Mfn2 in different types of cancers have been studied, including liver, breast and urinary bladder cancers [22-24]. Mfn2 is frequently lost in breast cancer, which has influence on breast cancer progression by a new mitochondria reprogramming pathway [17], and the PI3K-AKT-mTOR pathway plays an important role in the activation-induced downregulation of Mfn2 and the subsequent proliferation of resting human T cells [25]. In our early study, we found that the PTD4-apoptin fusion protein could induce HeLa cell apoptosis and upgrade Mfn2 expression [26].…”

Section: Introductionmentioning

confidence: 99%

Mitofusin-2 Triggers Cervical Carcinoma Cell Hela Apoptosis via Mitochondrial Pathway in Mouse Model

Wang

Liu

Guo

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cervical carcinoma continues to be one of the most dangerous cancer types, and more effective therapies are urgently needed for cervical carcinoma treatment. Mitochondria-associated Mitofusin 2 has influence on the progression of many cancers. In the current study, we aimed to focus on the cell apoptotic effects of Mfn2 on cervical carcinoma HeLa cells in vitro and to try to explore its underlying mechanisms. Moreover, we investigated the anticancer potential of Mfn2 in a cervical carcinoma mouse model. Methods: Adenovirus-Mfn2 (Adv-Mfn2) was used to deliver mfn2 into HeLa cells and tumour tissues in a nude mouse model. CCK-8, TUNEL assay, Western blot and immunohistochemical staining were performed to detect the effects of Mfn2. The mRNA level of Mfn2 was determined by quantitative realtime PCR (qRT-PCR) analysis. The effect of Mfn2 on cell apoptosis was investigated by flow cytometry. Flow cytometry was used to assess the change of the mitochondrial membrane potential of the cells treated with JC-1 assay. Mfn2, Bax, Bcl-2, cytochrome c, cleaved caspase-3, and cleaved caspase-9 protein levels were analysed by Western blot. Results: Data from CCK-8 and flow cytometry showed that Mfn2 could inhibit proliferation and induce apoptosis in a dose- and time-dependent manner in HeLa cells. JC-1 test results revealed that the membrane potential of the mitochondrial decreased in a dose-dependent manner in HeLa cells after Adv-Mfn2 treatment. The data from Western blot confirmed that higher cytosolic amounts of cytochrome c with increasing doses of Adv-Mfn2 signified the onset of the intrinsic apoptotic pathway. Levels of cleaved caspase-3 and cleaved caspase-9 increased in HeLa cells with Adv-Mfn2 treatment. We also found significant increases in the Bax level and a decreased Bcl-2 level with Adv-Mfn2 treatment. We further confirmed that Mfn2 could significantly inhibit the growth of the cervical tumour in the xenografted cervical carcinoma mouse model. After a 9-day-treatment, the tumours of the Adv-mfn2 group were inhibited and induced into apoptosis. The results demonstrated that the overexpression of Mfn2 could not only increase the levels of Bax and Bid in cervical tumour cells but also decrease the phosphorylation of Bad and the expression of Bcl-2. Conclusion: These studies suggested that the overexpression of Mfn2 could trigger cervical tumour apoptosis in vitro and in vivo, which was related to the mitochondrial pathway, and may provide a new treatment target for cervical carcinoma.

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Mitochondrial Reprogramming Regulates Breast Cancer Progression

Cited by 44 publications

References 44 publications

The anti-tumor effects of Mfn2 in breast cancer are dependent on promoter DNA methylation, the P21Ras motif and PKA phosphorylation site

The anti-tumor effects of Mfn2 in breast cancer are dependent on promoter DNA methylation, the P21Ras motif and PKA phosphorylation site

Genetic Mutation and Exosome Signature of Human Papilloma Virus Associated Oropharyngeal Cancer

Mitofusin-2 Triggers Cervical Carcinoma Cell Hela Apoptosis via Mitochondrial Pathway in Mouse Model

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