Selective induction of cell cycle arrest and apoptosis in human prostate cancer cells through adenoviral transfer of the melanoma differentiation-associated -7 (mda-7)/interleukin-24 (IL-24) gene.
We have previously reported that overexpression of the melanoma differentiation-associated gene -7 (mda-7) using a replication-defective adenovirus (Ad-mda7), results in tumor-specific growth suppression and induction of apoptosis in wide variety of cancer cells. In the present study, we investigated the antitumor activity of Ad-mda7 and the underlying mechanism in human prostate cancer cells and normal prostate epithelial cells. Overexpression of MDA-7 induced significant (P=.001) suppression of cell growth and apoptosis in prostate cancer cells (DU 145, LNCaP, and PC-3). In normal prostate epithelial cells (PrEC) some degree of growth inhibition but not apoptosis was observed. However, the inhibitory effects in normal cells were less compared to tumor cells. Growth inhibitory effects were mediated by the intracellular and not by extracellular MDA-7 protein. Molecular effectors that are involved in Ad-mda7-mediated tumor killing included activation of the caspase cascade, and the induction of G2 phase cell cycle arrest through the inhibition of Cdc25C pathway. These results demonstrate the mechanisms by which Ad-mda7 exerts its antitumor activity in human prostate cancer cells. The antitumor activity combined with previously reported antiangiogenic and proimmune properties of Ad-mda7 can serve as a potential therapeutic agent for treatment of primary and disseminated prostate cancer.
Saito
Yuji
Y
Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Miyahara
Ryo
R
Gopalan
Began
B
Litvak
Anya
A
Inoue
Satoshi
S
Shanker
Manish
M
Branch
Cynthia D
CD
Mhashilkar
Abner M
AM
Roth
Jack A
JA
Chada
Sunil
S
Ramesh
Rajagopal
R
D000256:Adenoviridae; D000704:Analysis of Variance; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018014:Gene Transfer Techniques; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D007378:Interleukins / Q000235:genetics* / Q000494:pharmacology; D008297:Male; D011471:Prostatic Neoplasms / Q000628:therapy*; D014407:Tumor Cells, Cultured; D000099180:Interleukin-24
D017304:Annexin A5; D007378:Interleukins; D000099180:Interleukin-24