N-(4-hydroxyphenyl)retinamide (4-HPR) modulates GADD45 expression in radiosensitive bladder cancer cell lines.
We previously demonstrated that N-(4-hydroxyphenyl)retinamide (4-HPR) and gamma-irradiation, when used in combination, had a synergistic effect in inducing apoptosis in bladder cancer cells, suggesting that 4-HPR may increase radiosensitivity in bladder cancer cells. To unravel molecular correlates in this radiosensitizing effect of 4-HPR, we examined the baseline and 4-HPR-induced expression of GADD45 to elucidate possible mechanisms by which 4-HPR enhanced the effect of gamma-irradiation in three bladder cancer cell lines. To investigate the role of p53 in mediating the radiosensitizing effect of 4-HPR, we also examined mutations in exons 5-9 by using direct sequencing and the levels of p53 expression by using RT-PCR and Western blot, before and after treatment with 4-HPR in these bladder cancer cell lines. Two cell lines had low expression of GADD45, and a dose-dependent increase in GADD45 expression induced by 4-HPR was found in bladder cancer cell lines without p53 mutations in exons 5-9. A combination of gamma-irradiation and 4-HPR showed a significantly greater effect in enhancing GADD45 expression than either agent used alone. The results indicate that the combined treatment with 4-HPR and gamma-irradiation has a stronger effect on GADD45 expression than the treatment with either agent alone, which suggests that the two agents may have an additive/synergistic effect. However, a normal p53 function appears to be necessary for the dose-dependent induction of GADD45 by 4-HPR. Once our results are verified and replicated by other investigators, 4-HPR may have a potential clinical implication in effectively treating bladder cancer in combination with low-gamma-irradiation therapy.
Zou
Changping
C
Department of Obstetrics and Gynecology, The University of Texas-Houston Medical School, Houston, TX 77030, USA.
Guan
Yongli
Y
Zou
Changchun
C
Wang
Jian
J
Wang
Li-E
LE
Liebert
Monica
M
Grossman
H Barton
HB
Wei
Qingyi
Q
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017313:Fenretinide / Q000494:pharmacology*; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016158:Genes, p53; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D011836:Radiation Tolerance; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy; D000097642:GADD45 Proteins
D000970:Antineoplastic Agents; D017313:Fenretinide; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D000097642:GADD45 Proteins