Rho/ROCK pathway as a target of tumor therapy.
This study emphasizes the importance of Rho/ROCK pathway in lovastatin-induced apoptosis as replenishment with exogenous isoprenoid, geranylgeranylpyrophosphate (GGPP), resulted in inhibition of apoptosis in cultured tumor cells. Treatment of C6 glioma cells with Toxin B and exoenzyme C3 resulted in cell death suggesting the role of geranylgeranylated protein(s) in the survival of glioma cells. Relative apoptotic death observed in cells transfected with dominant negative constructs of RhoA, Rac, and cdc42 imply Rho A as playing the major role in cell survival. Furthermore, the inhibition of Rho A kinase (ROCK), a direct downstream effector of Rho A, by Y-27632 or dominant negative of ROCK, induced apoptosis in glioma cells. These findings indicate that RhoA/ROCK pathway is involved negatively in the regulation of glioma cell death pathway. Moreover, in vivo studies of lovastatin treatment in animals implanted with C6 glioma cell tumors also resulted in smaller tumor size and induced apoptosis in the tumor tissue. The implantation of stably transfected C6 glioma cells with expression vector of C3 exoenzyme, dominant negative of RhoA and ROCK, resulted in significant smaller tumor mass, further establishing the importance of geranylgeranylated proteins, specifically RhoA and its downstream effecter ROCK, in cell survival and tumor genesis.
Rattan
R
R
Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Giri
S
S
Singh
A K
AK
Singh
I
I
D000577:Amides / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015139:Blotting, Southern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D053938:DNA Fragmentation / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins; D008148:Lovastatin / Q000627:therapeutic use*; D008297:Male; D008798:Mevalonic Acid / Q000008:administration & dosage; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D014407:Tumor Cells, Cultured; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D000577:Amides; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011106:Polyisoprenyl Phosphates; D011725:Pyridines; D013778:Tetrazolium Salts; D013844:Thiazoles; C108830:Y 27632; D008148:Lovastatin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020169:Caspases; D020742:rhoA GTP-Binding Protein; C022616:thiazolyl blue; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid