Adenovirus-expressed human hyperplasia suppressor gene induces apoptosis in cancer cells.
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 (DeltaPsim) 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.
Wu
Lina
L
Center for Human Disease Genomics, Health Science Center, Peking University, 38 Xue-yuan Road, Beijing, 100083, P.R. China.
Li
Zhixin
Z
Zhang
Yingmei
Y
Zhang
Pei
P
Zhu
Xiaohui
X
Huang
Jing
J
Ma
Teng
T
Lu
Tian
T
Song
Quansheng
Q
Li
Qian
Q
Guo
Yanhong
Y
Tang
Jian
J
Ma
Dalong
D
Chen
Kuang-Hueih
KH
Qiu
Xiaoyan
X
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D012333:RNA, Messenger; D045304:Cytochromes c