Roscovitine up-regulates p53 protein and induces apoptosis in human HeLaS(3) cervix carcinoma cells.
Exposure of human HeLaS(3) cervix carcinoma cells to high doses of conventional cytostatic drugs, e.g. cisplatin (CP) strongly inhibits their proliferation. However, most cytostatic agents are genotoxic and may generate a secondary malignancy. Therefore, therapeutic strategy using alternative, not cytotoxic drugs would be beneficial. Inhibition of cyclin-dependent kinases (CDKs) by pharmacological inhibitors became recently a promising therapeutic option. Roscovitine (ROSC), a selective CDK inhibitor, efficiently targets human malignant cells. ROSC induces cell cycle arrest and apoptosis in human MCF-7 breast cancer cells. ROSC also activates p53 protein. Activation of p53 tumor suppressor protein is essential for induction of apoptosis in MCF-7 cells. Considering the fact that in HeLaS(3) cells wt p53 is inactivated by the action of HPV-encoded E6 oncoprotein, we addressed the question whether ROSC would be able to reactivate p53 protein in them. Their exposure to ROSC for 24 h induced cell cycle arrest at G(2)/M and reduced the number of viable cells. Unlike CP, ROSC in the used doses did not induce DNA damage and was not directly cytotoxic. Despite lack of detectable DNA lesions, ROSC activated wt p53 protein. The increase of p53 levels was attributable to the ROSC-mediated protein stabilization. Further analyses revealed that ROSC induced site-specific phosphorylation of p53 protein at Ser46. After longer exposure, ROSC induced apoptosis in HeLaS(3) cells. These results indicate that therapy of HeLaS(3) cells by ROSC could offer an advantage over that by CP due to its increased selectivity and markedly reduced risk of generation of a secondary cancer.
Cell Cycle Regulation Group, Div.: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria. jozefa.gadek-wesierski@meduniwien.ac.at
Józefa
J
Wesierska-Gadek
Stefanie
S
Wandl
Matthias P
MP
Kramer
Christian
C
Pickem
Vladimir
V
Krystof
Susanne B
SB
Hajek
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D006367:HeLa Cells; D006801:Humans; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D000970:Antineoplastic Agents; D011687:Purines; D016159:Tumor Suppressor Protein p53; D000077546:Roscovitine