Prostate Cancer Cell Cycle Regulators: Response to Androgen Withdrawal and Development of Androgen Independence

Abstract

Early events included a decrease in androgen receptor expression, followed by a short-term increase in expression of the p53 and p21/WAF1 proteins and a marked decrease in the Ki67 proliferative index. Mid-to-late events included progressive and sustained increases in p27 and p16 protein expression, a decrease in retinoblastoma protein expression, and an increase in the transcription factor E2F1. Changes in apoptosis (programmed cell death) were not observed at any time after androgen withdrawal. These data suggest that androgen withdrawal results in a cell stress response, in which increased p53 protein produces a cell cycle arrest, without activation of p53-mediated apoptosis. The proliferative index is further decreased through the action of the cyclin-dependent kinase inhibitors p27 and p16. Androgen-independent sublines emerged 80-400 days after androgen withdrawal, and these sublines had variable growth phenotypes but were associated with mdm2 protein overexpression and increased expression of cyclin D1. These results indicate that tumor regression in this human prostate cancer model is due to cell cycle arrest rather than to apoptosis and that the emergence of androgen independence is associated with a release from cell cycle arrest.

Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells

“…Androgen also inhibits the expression (Rokhlin et al, 2005) and nuclear accumulation of p53 (Nantermet et al, 2004). Withdrawal of androgen or application of an antiandrogen can increase p53 expression and activity (Agus et al, 1999;Bouchal et al, 2005). While this may explain the high basal expression of SESN1 as shown here in the absence of androgen, a mechanism as to why AR-siRNA reduced these levels remains elusive and the subject of further investigation ongoing in our lab.…”

Exogenous p27KIP1 expression induces anti-tumour effects and inhibits the EGFR/PI3K/Akt signalling pathway in PC3 cells

“…Elevated Akt activity may have a profound role in the progression of human prostate cancer. Akt regulates many of the processes associated with metastatic progression and the emergence of AIPC cells, such as diminished apoptotic response [33] and release from the cell cycle control that follows androgen ablation [34]. Akt can dampen the normal apoptotic response by suppressing the activity of numerous pro-apoptotic proteins, including Bad, caspase-9 and the Forkhead family of transcription factors [35][36][37].…”

The Complex Role of AR Signaling After Cytotoxic Insult: Implications for Cell Cycle Based Chemotherapeutics

“…Often, substantial tumor remission is observed upon administration of hormone therapy, resulting from both tumor cell death and cell cycle arrest. [14][15][16] However, this period of remission is transient, as recurrent tumors arise within a median time of 2-3 years. 7,17 These "androgen-independent" tumors almost invariably reoccur as a result of restored AR activity.…”