Differential effects of RhoA signaling on anticancer agent-induced cell death.
Substantial evidence exists to support a role for RhoA signaling in adhesion and cytoskeletal reorganization, while relatively less is known about the participation of RhoA on cell survival. We provide evidence that RhoA functions as a differential modulator of apoptosis induced by anticancer agents. Specifically, both RhoA and caRhoA induce statistically significant resistance to statin, etoposide, 5-FU and taxol while increasing sensitivity to vincristine (all p<0.001). The IC50 values for statin, etoposide, 5-fluorouracil (5-FU) and taxol in caRhoA transfectant were 8.70+/-0.74, 4.08+/-0.12, 4.12+/-0.12 microg/ml and 3.84+/-0.16 ng/ml, respectively, whereas the respective IC50 values in the mock-transfected control were 3.40+/-0.21, 1.12+/-0.06, 1.21+/-0.06 microg/ml and 2.84+/-0.15 ng/ml. This represented a 2.6-, 3.5-, 3.2- and 1.4-fold resistance to statin, etoposide, 5-FU and taxol, respectively. In contrast, caRhoA increased sensitivity to vincristine, decreasing IC50 values from 4.61+/-0.46 to 3.73+/-0.44 ng/ml (p<0.001). Western blot analysis demonstrated that RhoA mediates induction of E2F-1, Cdk2 and PCNA, accompanying concurrent reduction in p21 and p27. However, cleavage assays of poly (ADP-ribose) polymerase, BID, caspase-8 and caspase-3 indicate that the cell growth modulation mediated by RhoA in response to these anticancer agents occurs through the inhibition of apoptosis. Taken together, these results indicate that RhoA differentially modulates cancer cell death depending on the anticancer agent.
Kang
Won Ki
WK
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 135-710 Seoul, Korea. wkkang@smc.samsung.co.kr
Lee
Inkyoung
I
Ko
Ukyoung
U
Park
Chaehwa
C
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000502:physiology*
D000970:Antineoplastic Agents; C066737:RHOA protein, human; D014750:Vincristine; D005047:Etoposide; D008148:Lovastatin; D020169:Caspases; D020742:rhoA GTP-Binding Protein; D017239:Paclitaxel; D005472:Fluorouracil