Differential expression of AP-1 transcription factors in human prostate LNCaP and PC-3 cells: role of Fra-1 in transition to CRPC status

Abstract

Androgen receptor (AR) signaling axis plays a vital role in the development of prostate and critical in the progression of prostate cancer. Androgen withdrawal initially regresses tumors but eventually develops into aggressive castration-resistant prostate cancer (CRPC). Activator Protein-1 (AP-1) transcription factors are most likely to be associated with malignant transformation in prostate cancer. Hence, to determine the implication of AR and AP-1 in promoting the transition of prostate cancer to the androgen-independent state, we used AR-positive LNCaP and AR-negative PC-3 cells as an in vitro model system. The effect of dihydrotestosterone or anti-androgen bicalutamide on the cell proliferation and viability was assessed by MTT assay. Expression studies on AR, marker genes-PSA, TMPRSS2, and different AP-1 factors were analyzed by semi-quantitative RT-PCR and expressions of AR and Fra-1 proteins were analyzed by Western blotting. Dihydrotestosterone induced the cell proliferation in LNCaP with no effect on PC-3 cells. Bicalutamide decreased the viability of both LNCaP and PC-3 cells. Dihydrotestosterone induced the expression of AR, PSA, c-Jun, and Fra-1 in LNCaP cells, and it was c-Jun and c-Fos in case of PC-3 cells, while bicalutamide decreased their expression. In addition, constitutive activation and non-regulation of Fra-1 by bicalutamide in PC-3 cells suggested that Fra-1, probably a key component, involved in transition of aggressive androgen-independent PC-3 cells with poor prognosis.

Nobiletin, a citrus polymethoxyflavone, enhances the effects of bicalutamide on prostate cancer cellsviadown regulation of NF-κB, STAT3, and ERK activation

“…These ndings agree with earlier studies reported. 6,25 One of studies reveals that the mechanisms of BCT-induced apoptosis in androgen-independent prostate cancer cells is partially reliant on calpain activity and pan-caspase inhibition. 31 However, the detailed molecular mechanisms of how bicalutamide inhibits the growth of androgen-independent prostate cancer cells remains unclear.…”

“…These results agree with previous studies. 6,24,25 NBT or BCT at 20-50 mM concentrations had small to moderate effects on prostate cancer cells, which allow us to determine the potential synergistic effect of combinations of the two compounds. Therefore we chose 20-50 mM for combination studies.…”

Mechanism of Anti-Cancer Activity of Curcumin on Androgen-Dependent and Androgen-Independent Prostate Cancer

“…Constitutive AP-1 activity in PCa disease is associated with poor clinical outcomes through modulating cancer-related genes expression involved in inflammation, cell proliferation, neoplastic transformation and metastasis [181][182][183]. Studies have reported that the correlation between Fos (Fra-1) and Jun family (c-Jun) proteins has been associated with tumour growth in multiple types of cancer.…”

“…Other studies reported that the increased cytoplasmic phosphorylated ATF proteins family (ATF2) in PCa compared to normal prostate cells suggest that altered localisation of ATF2 may contribute to clinical progression of PCa [187]. Meanwhile, the activation of the member of Fos family (Fra-1) and Jun family (c-Jun) proteins have associated with the progression to AIPC state [182,188]. Elevated levels of Jun and Fos proteins in mouse models of PCa was also correlated with prostate tumorigenesis, whereas the levels of Jun proteins alone is correlated with disease recurrence [189].…”

Activation of MAPK and Cyclin D1/CDK4 in Malignant Transformation of Human Embryonic Lung Fibroblasts Induced by Silica and Benzopyrene

“…The activation of AP-1 is regulated by MAPK. The activation of each member of the MAPK subfamily has a specific phosphorylation cascade (Kavya et al, 2017). ERK pathway regulates cell growth and differentiation.…”