Adenovirus-expressed human hyperplasia suppressor gene induces apoptosis in cancer cells

Abstract

Hyperplasia suppressor gene (HSG), also called human mitofusin 2, is a novel gene that markedly suppresses the cell proliferation of hyperproliferative vascular smooth muscle cells from spontaneously hypertensive rat arteries. This gene encodes a mitochondrial membrane protein that participates in mitochondrial fusion and contributes to the maintenance and operation of the mitochondrial network. In this report, we showed that an adenovirus vector encoding human HSG (Ad5-hHSG) had an antitumor activity in a wide range of cancer cell lines. We further focused on the lung cancer cell line A549 and the colon cancer cell line HT-29 and then observed that Ad5-hHSG induced apoptosis both in vitro and in vivo. Confocal laser scanning microscopy and electron microscopy revealed that cells infected with Ad5-hHSG formed dose-dependent perinuclear clusters of fused mitochondria. Adenovirus-mediated hHSG overexpression induced apoptosis, cell cycle arrest, mitochondrial membrane potential (#8m) reduction and release of cytochrome c, caspase-3 activation, and cleavage of PARP in vitro. Overexpression of hHSG also significantly suppressed the growth of subcutaneous tumors in nude mice both ex vivo and in vivo. In addition, Ad5-hHSG increased the sensitivity of these cell lines to two chemotherapeutic agents, VP16 and CHX, and radiation. These results suggest that Ad5-hHSG may serve as an effective therapeutic drug against tumors.

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

“…Using Western blot analysis and RT-PCR analysis, we found that Mfn2 protein and mRNA levels were significantly lower in CRC tissues than in corresponding normal tissues. Overexpression of Mfn2 protein mediated by adenovirus has a significant anti-proliferative effect in a wide range of cancer cell lines [8]. Our results indicate that Ad-Mfn2 also had a significant anti-proliferative effect in HCT116, HT-29, and SW480 cells.…”

“…The anti-proliferative effect of Mfn2 is comparable to that of the well-known tumor suppressor p53 [5,8]. We demonstrated previously that Mfn2 is a novel p53-inducible target gene in hepatocellular carcinoma cells [9].…”

Sodium valproate inhibits MDA-MB-231 breast cancer cell migration by upregulating NM23H1 expression

“…Optical density (OD) was read at 570 nm using a spectrophotometer microplate reader (Labsystems, Finland). The inhibition of islet cells caused by different concentrations of VPA was calculated using the formula: inhibition rate (%) = 100 x (1 -[OD drug exposure / OD control ]) (Wu et al, 2008).…”

Krüppel-like factor 4 interacts with p300 to activate mitofusin 2 gene expression induced by all-trans retinoic acid in VSMCs

“…Several lines of evidence indicate that mfn-2 modulates mitochondrial metabolism by regulating mitochondrial membrane potential, fuel oxidation, and the oxidative phosphorylation system [11,12] . Recent evidence also shows that mfn-2 inhibits tumor cell proliferation and increases their sensitivity to chemotherapy and radiotherapy even above p53 [13] . In addition, recent study has shown that mfn-2 exhibits a profound anti-proliferative effect on VSMCs in vitro and in vivo via inhibition of the Ras-Raf-MEK-ERK1/2 MAPK signaling pathway [14] , and promotes VSMC and cardiomyocyte apoptosis via the mitochondrial death pathway [15,16] .…”