Bcl-2 and Bcl-x(L) differentially protect human prostate cancer cells from induction of apoptosis by melanoma differentiation associated gene-7, mda-7/IL-24.
Subtraction hybridization identified melanoma differentiation associated gene-7, mda-7, in the context of terminally differentiated human melanoma cells. Based on its structure, cytokine-like properties and proposed mode of action, mda-7 has now been classified as IL-24. When expressed by means of a replication-incompetent adenovirus, Ad.mda-7 induces apoptosis in a broad range of cancer cells, without inducing harmful effects in normal fibroblast or epithelial cells. These unique properties of mda-7/IL-24 suggest that this gene will prove beneficial for cancer gene therapy. We now demonstrate that Ad.mda-7 decreases viability by induction of apoptosis in hormone-responsive (LNCaP) and hormone-independent (DU-145 and PC-3) human prostate carcinomas, without altering growth or survival in early-passage normal human prostate epithelial cells (HuPEC). Ad.mda-7 causes G(2)/M arrest and apoptosis in LNCaP (p53-wildtype), DU-145 (p53 mutant, Bax-negative) and PC-3 (p53-negative) prostate carcinomas, but not in HuPEC. Apoptosis induction correlated with changes in the ratio of pro- to antiapoptotic Bcl-2 protein family members. A potential functional role for changes in bcl-2 family gene expression in Ad.mda-7-induced apoptosis was suggested by the finding that forced overexpression of bcl-x(L) or bcl-2 differentially diminished the apoptotic effect of Ad.mda-7 in prostate carcinomas. These results confirm that induction of apoptosis by the mda-7/IL-24 gene in prostate cancer cells is Bax- and p53-independent and is mediated by mitochondrial pathways involving bcl-2 family gene members. The mda-7/IL-24 gene represents a new class of cancer-specific apoptosis-inducing genes with obvious potential for the targeted gene-based therapy of human prostate cancer.
Lebedeva
Irina V
IV
Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Sarkar
Devanand
D
Su
Zao-Zhong
ZZ
Kitada
Shinichi
S
Dent
Paul
P
Stein
C A
CA
Reed
John C
JC
Fisher
Paul B
PB
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D020169:Caspases / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival; D053938:DNA Fragmentation; D016195:G2 Phase; D016147:Genes, Tumor Suppressor; D006801:Humans; D007378:Interleukins / Q000502:physiology*; D008297:Male; D008938:Mitosis; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000628:therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D051020:bcl-X Protein; D000099180:Interleukin-24
D020169:Caspases; D007378:Interleukins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D000099180:Interleukin-24; C494811:BCL2L1 protein, human