The refractoriness of prostate cancer to androgen suppression is the landmark of clinically aggressive disease. In this study, the androgen-dependent LNCaP prostate cancer cells were transfected with the mutated c-Ha-ras gene from the T24 human bladder cancer. The derivative clone overexpressing T24-ras (LNCap(T24-ras)) proliferated in androgen-depleted medium and showed increased growth. Protein isoprenylation and p21ras famesylation in LNCaP(T24-ras) cells were tested in the presence of phenylacetate to document a possible relationship with the drug-induced inhibition of cell proliferation. Phenylacetate is a differentiation inducer that down-regulates in vitro the expression of the myc oncogene and activates the human peroxisome proliferator-activated nuclear receptor involved in cell growth regulation. The drug inhibited protein isoprenylation and p21ras famesylation in LNCaP(T24-ras) cells; IC50 values were 3.1 and 3.3 mM, respectively, compared with controls. The drug reduced the cellular levels of endogenous farnesyl-PP (mean IC50 = 3.5 mM) and inhibited activation of the p21ras downstream target, p42(MAPK)/ERK2. LNCaP(T24-ras) was more sensitive than the parental line to both growth inhibition (mean IC50 = 3.01 and 7.1 mM, respectively) and apoptosis by phenylacetate. Exogenous farnesyl- and geranylgeranyl-PP indeed reduced the effects of the drug on proliferation and apoptosis in LNCaP(T24-ras) cells. In conclusion, the inhibition of protein isoprenylation and p21ras famesylation by phenylacetate resulted in increased chemosensitivity of the androgen-independent LNCap(T24-ras) cells compared with LNCaP, and this effect might contribute to the pharmacological activity of the drug.
|Autori interni:||DANESI, ROMANO|
|Autori:||DANESI R; NARDINI D; BASOLO F; DEL TACCA M; SAMID D; MYERS CE|
|Titolo:||Phenylacetate inhibits protein isoprenylation and growth of the androgen-independent LNCaP prostate cancer cells transfected with the T24 Ha-ras oncogene|
|Anno del prodotto:||1996|
|Appare nelle tipologie:||1.1 Articolo in rivista|