Prostate cancer cells generated during intermittent androgen ablation acquire a growth advantage and exhibit changes in epidermal growth factor receptor expression.

Intermittent androgen ablation is a palliative treatment option for advanced prostate cancer which is associated with less side effects, improved quality of life of patients, and reduced costs. Regulation of growth and survival of prostate cancer cells during intermittent androgen withdrawal has not been studied in appropriate models yet. Two cycles of androgen withdrawal and supplementation were performed in human prostate cancer cells LNCaP in vitro. Proliferation of prostate cancer cell sublines established after intermittent androgen withdrawal was assessed in the absence or presence of epidermal growth factor (EGF) by protein determination. Cell cycle was analyzed with a flow cytometer. EGF was measured in the supernatants of LNCaP sublines with a commercial ELISA. EGF receptor mRNA and protein were determined by real-time PCR and Western blot, respectively. Basal proliferation rate of all newly generated LNCaP sublines increased over that of the parental LNCaP cell line. The highest stimulation of proliferation by exogenous EGF was observed in parental LNCaP cells. In each LNCaP derivative established during intermittent androgen withdrawal, the percentage of cells in the S phase of cell cycle was higher than that in parental LNCaP cells. EGF levels did not increase during intermittent androgen ablation. The expression of EGF receptor protein decreased following each cycle of androgen ablation and increased subsequently after androgen supplementation. EGF receptor (EGFR) mRNA was regulated in a similar manner in LNCaP derivatives established during the second cycle of intermittent withdrawal. Changes in the expression of the EGF receptor occur during intermittent androgen ablation but they cannot be solely responsible for increased basal proliferation. Alternatively, other ligands and receptors of the EGF system may become overexpressed during prolonged withdrawal and supplementation of androgenic hormones in prostate cancer therapy.

Hobisch A ，Fiechtl M ，Sandahl-Sorensen B ，Godoy-Tundidor S ，Artner-Dworzak E ，Ramoner R ，Bartsch G ，Culig Z ... -  《PROSTATE》

Increased expression of heparin binding EGF (HB-EGF), amphiregulin, TGF alpha and epiregulin in androgen-independent prostate cancer cell lines.

Tørring N ，Jørgensen PE ，Sørensen BS ，Nexø E ... -  《ANTICANCER RESEARCH》

Complex post-transcriptional regulation of EGF-receptor expression by EGF and TGF-alpha in human prostate cancer cells.

Seth D ，Shaw K ，Jazayeri J ，Leedman PJ ... -  《-》

Prostate cancer cells (LNCaP) generated after long-term interleukin 6 (IL-6) treatment express IL-6 and acquire an IL-6 partially resistant phenotype.

Hobisch A ，Ramoner R ，Fuchs D ，Godoy-Tundidor S ，Bartsch G ，Klocker H ，Culig Z ... -  《CLINICAL CANCER RESEARCH》

The androgen receptor pathway is by-passed in prostate cancer cells generated after prolonged treatment with bicalutamide.

Experimental work in various prostate cancer models revealed that the androgen receptor is frequently upregulated and implicated in tumor progression. However, little attention has been paid to the androgen receptor-signaling pathway in the development of therapy resistance in patients who receive chronic treatment with a non-steroidal anti-androgen. We have generated a novel subline, LNCaP-Bic, after prolonged treatment with androgen and bicalutamide in vitro. Proliferation of LNCaP-Bic cells in the absence or presence of androgen, tocopherol succinate, and/or bicalutamide was assessed by cell counting. Androgen receptor expression was determined by Western blot. Luciferase activity was measured in cells transfected with an androgen-responsive reporter. In basal conditions, proliferation of LNCaP-Bic cells increased more than threefold over that of control LNCaP cells. Neither synthetic androgen R1881 nor bicalutamide showed any effect on LNCaP-Bic growth in vitro. Androgen receptor expression did not differ between the cell subline generated in the presence of bicalutamide and parental LNCaP cells. The ability of R1881 to induce reporter gene activity in LNCaP-Bic cells was reduced by 56%. Tocopherol succinate caused inhibition of proliferation only in the parental cell line although the androgen receptor and prostate-specific antigen were down regulated by the vitamin E derivative in both parental LNCaP and LNCaP-Bic cells. Androgen receptor-mediated signal transaction is not enhanced in cells selected in the presence of bicalutamide. Our data may suggest that a more differentiated approach in targeting the androgen receptor is needed in prostate cancers that become resistant to classic endocrine treatment.

Hobisch A ，Fritzer A ，Comuzzi B ，Fiechtl M ，Malinowska K ，Steiner H ，Bartsch G ，Culig Z ... -  《PROSTATE》