Cell-cycle arrest at G2/M and proliferation inhibition by adenovirus-expressed mitofusin-2 gene in human colorectal cancer cell lines

Abstract

The mitofusin-2 (Mfn2) is a novel gene characterised as a cell proliferation inhibitor. Mfn2 protein over-expression, mediated by an adenovirus, has a significant anti-proliferative effect in hepatoma carcinoma cells. However, there is no report on the effect of Mfn2 on colorectal cancer (CRC). In this study, we found that Mfn2 protein and mRNA levels were downregulated in CRC tissues compared to nearby normal tissues. An adenovirus encoding the complete Mfn2 open reading frame (Ad-Mfn2) exhibited a prominent anti-proliferative effect in the CRC cell lines HCT 116, HT-29, and SW480. AdMfn2 infection significantly inhibited the proliferation of CRC cells compared with Ad-GFP infection. Mfn2 overexpression resulted in a cell-cycle arrest at G2/M phase in CRC cells, and it increased the levels of p-cdc2 (Tyr15) and Myt1; however, the levels of cyclin B1 and p-ERK1/2 was reduced. Mfn2 overexpression aslo increased the levels of active caspase-3 and cleaved PARP. Taken together, these findings indicate that Mfn2 has a significant anti-proliferative effect in CRC cells using adenoviral vectors.

Regulation of mitochondrial morphology and cell cycle by microRNA-214 targeting Mitofusin2

“…Increase in MFN2 led to cell cycle arrest at G2/M phase [15]. Also percentage of cells in S-phase was higher in HD mutant cell line STHdh Q111/Q111 compared to normal STHdh Q7/7 cell line [24].…”

“…MFN2 is also shown to be involved in cell proliferation [13] and apoptosis [14]. Increase in MFN2 leads to cell cycle arrest at G2/M phase [15]. Abortive reactivation of cell cycle and up regulation of several cell cycle related proteins have been implicated in neurodegenerative diseases and proposed to be the cause of neurodegeneration [16e18].…”

E2F1 activates MFN2 expression by binding to the promoter and decreases mitochondrial fission and mitophagy in HeLa cells

“…Antiproliferative and antiapoptotic activities of MFN2 have been shown to mediate through Phosphatidylinositol 3 kinase/Akt pathway in breast cancer cells . MFN2 is required for excitotoxicity induced mitochondrial fragmentation, inhibition of cell proliferation, cell cycle arrest at G2/M, increased apoptosis , maintenance of haematopoietic stem cells through buffering intracellular Ca ++ levels, nuclear localization of nuclear factor of activated T cells , mitophagy and autophagy . Decreased expression of MFN2 causes mitochondrial dysfunction, changes calcium homeostasis, increases translocation of Bax to mitochondria and delay apoptosis .…”

Mitochondrial Fragmentation Due to Inhibition of Fusion Increases Cyclin B through Mitochondrial Superoxide Radicals

“…This is consistent with the delayed mitotic exit we observe. It is interesting to note that the inactivation of mitofusin is associated with lung cancers [ 53 ], breast cancer [ 54 ], colorectal cancer [ 55 ] and hepatocellular carcinoma [ 56 ]. While Ras and Raf are implicated in these, especially where Mfn2 is concerned, our results indicate there could be another pathway involving mitochondrial superoxide by which cancer cells could up-regulate cyclin B and hyperproliferate.…”