Adenovirus-mediated restoration of expression of the tumor suppressor gene DLC1 inhibits the proliferation and tumorigenicity of aggressive, androgen-independent human prostate cancer cell lines: prospects for gene therapy.
Our recent study showing highly recurrent loss of function of DLC1 (deleted in liver cancer 1), a tumor suppressor gene in primary prostate carcinoma (PCA), implicates this gene in the pathogenesis of this disease. To evaluate the response of PCA to oncosuppressive activity of DLC1, we examined now the effects of adenoviral vector for human DLC1 transduction into the DLC1-deficient, androgen-independent (AI) and aggressive human PCA cell lines PC-3 and C4-2-B2. Adenovirus-mediated restoration of DLC1 expression inhibited the proliferation, invasiveness and anchorage-independent growth of PC-3 and C4-2-B2 cells in vitro as well as the tumorigenicity of PC-3 cells in nude mice. It also induced cell-cycle arrest, inhibited the activation of RhoA and the formation of actin stress fibers. DLC1 induced apoptosis in C4-2-B2 cells, whereas it did not elicit such an effect in PC-3 cells. The abundance of the antiapoptotic protein Bcl-2 was greater in PC-3 cells than in C4-2-B2 cells, and PC-3 cells were rendered sensitive to DLC1-induced apoptosis by treatment with the Bcl-2 inhibitor HA14-1. These results suggest that adenovirus-mediated DLC1 transfer, alone or together with other agents, such as inhibitors of Bcl-2 or histone deacetylase, might prove effective in the treatment of aggressive, AI-PCA.
Guan
M
M
Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4262, USA.
Tripathi
V
V
Zhou
X
X
Popescu
N C
NC
D000256:Adenoviridae / Q000235:genetics*; D000728:Androgens / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020690:GTPase-Activating Proteins; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
D000728:Androgens; C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; D025521:Tumor Suppressor Proteins