Cellular growth inhibition by FK778 is linked to G1 arrest or S phase accumulation, dependent on the functional status of the retinoblastoma protein.
The malononitrilamide FK778 is a novel immunosuppressive agent with antiproliferative activities. To gain insight into the molecular mechanism of FK778-mediated growth inhibition, we analyzed cells which differ in their p53 status and functionality of retinoblastoma protein (pRb). FK778 acted as a broad inhibitor of cell proliferation independent of the p53 or pRb status. However, the mechanism of FK778-mediated growth inhibition differed, leading either to cell cycle arrest in G1, or cell accumulation in S phase. This differential response was linked to the phosphorylation status of pRb. In addition, since FK778 was reported to exhibit antiviral activities, we analyzed the effect of FK778 on the growth stimulatory human papillomavirus (HPV)-16 and -18 E7 genes. Although growth of HPV-positive cells was strongly inhibited by FK778, we did not observe significant effects on viral E7 expression, indicating that the antiproliferative effect is not linked to an antiviral activity of FK778.
Hoppe-Seyler
Karin
K
Molecular Therapy of Virus-Associated Cancers (F065), German Cancer Research Center, D-69120 Heidelberg, Germany. k.hoppe-seyler@dkfz.de
Weigand
Kilian
K
Lohrey
Claudia
C
Hoppe-Seyler
Felix
F
Sauer
Peter
P
D000480:Alkynes / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D016193:G1 Phase / Q000187:drug effects*; D006367:HeLa Cells; D052162:Human papillomavirus 16 / Q000378:metabolism; D052161:Human papillomavirus 18 / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology*; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis; D050725:Papillomavirus E7 Proteins; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000480:Alkynes; D000998:Antiviral Agents; D004268:DNA-Binding Proteins; C052633:E7 protein, Human papillomavirus type 18; D007555:Isoxazoles; D009570:Nitriles; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide