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Research Articles: Therapeutics, Targets, and Development

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

¹ Center for Human Disease Genomics, Health Science Center and ² Institute of Cardiovascular Science and Institute of Molecular Medicine, Peking University, Beijing, China

Requests for reprints: Xiaoyan Qiu, Center for Human Disease Genomics, Health Science Center, Peking University, 38 Xue-yuan Road, Beijing, 100083, P.R. China. Phone: 86-10-82802846-5035. Fax: 86-10-82801149. E-mail: qiuxy{at}bjmu.edu.cn or Kuang-Hueih Chen. E-mail: ChenKu{at}grc.nia.nih.gov

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 (m) 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. [Mol Cancer Ther 2008;7(1):222–32]

Grant support: National High Technology Research and Development Program of China grant 2002AA216131.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: L. Wu and Z. Li contributed equally to this work.

Present address for Zhixin Li: Department of Integrated Traditional Chinese Medicine and Western Medicine, Health Science Center, Peking University, 38 Xue-yuan Road, Beijing, 100083, P.R. China.

³ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 6/ 8/07; revised 10/ 1/07; accepted 12/ 3/07.