Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor

Abstract

Classic work by Huggins and Hodges demonstrated that human prostate cancer regresses dramatically during antihormonal therapy but recurs frequently with androgen independence. Perturbations in the androgen receptor (AR) and PTEN-AKT signaling axes are significantly correlated with the progression of prostate cancer. Genetic alterations of the AR cause receptor hypersensitivity, promiscuity, and androgen-independent receptor transactivation. Prostate cancers maintain an elevated AKT activity through the loss of PTEN function or the establishment of autocrine signaling by growth factors and cytokines. We used an in vivo prostate regeneration system to investigate the biological potency of the potential crosstalk between these two signal transduction pathways. We demonstrate a direct synergy between AKT and AR signaling that is sufficient to initiate and progress naïve adult murine prostatic epithelium to frank carcinoma and override the effect of androgen ablation. Both genotropic and nongenotropic signals mediated by AR are essential for this synergistic effect. However, phosphorylation of AR by AKT at Ser-213 and Ser-791 is not critical for this synergy. These results suggest that more efficient therapeutics for advanced prostate cancer may need to target simultaneously AR signaling and AKT or the growth factor receptor tyrosine kinases that activate AKT.prostate regeneration ͉ tissue structure F undamental changes take place in androgen receptor (AR) signaling during prostate cancer progression (1, 2). AR signaling mediates cell differentiation and growth inhibition in the normal adult human and murine prostate (3-6). For example, AR can induce the expression of the luminal cell differentiation marker prostate-specific antigen (PSA) and the cell-cycle inhibitor p21. Transgenic mice harboring a prostatespecific AR transgene develop normal prostate tissues or show mild hyperplasia after a long latency period (7,8). However, cell autonomous androgen signals stimulate the proliferation of human or rodent AR-positive cancer cells (9). AR signaling also plays a critical role in the transition of prostate cancer from the androgen-dependent to -independent stage. Increased transcriptional level of AR mRNA has been demonstrated as the most common molecular determinant of resistance to antiandrogen therapy in a xenograft castration model (1).Loss of function of PTEN and activation of AKT are significantly correlated with the progression of prostate cancer (10). In vivo studies showed that murine prostatic intraepithelial neoplasia (mPIN) develops in transgenic mice expressing activated AKT1 specifically in the prostate (11). Previous in vitro studies using long-term passaged cancer cell lines have demonstrated that PTEN and AKT are, respectively, negative and positive modulators of AR transcriptional activity (12-15). Some papers have reported that AKT negatively regulates AR protein levels and transcriptional activity at the posttranscriptional (16) and posttranslational (17, 18) levels.We have modified and improved a p...

ETS family transcription factors collaborate with alternative signaling pathways to induce carcinoma from adult murine prostate cells

“…(29) and results in activation of the PI3K pathway. We demonstrated that increased PI3K signaling via shRNA-mediated PTEN knockdown or overexpression of an activated form of AKT in murine prostate cells causes PIN lesions in the tissue-regeneration model (30,31). In this study, we combined overexpression of ERG and activated AKT and found that grafts derived from coinfected adult prostate cells weighed 2-3 times more than grafts generated from AKT or ERG overexpression alone (Fig.…”

Epithelial Stem Cells of the Prostate and Their Role in Cancer Progression

“…Alterations in androgen receptor signaling causing receptor hypersensitivity, promiscuity, or androgen-independent receptor trans-activation are also a common feature of prostate cancer . When additional AR is introduced in addition to constitutively active AKT, regenerated grafts contain androgen-independent adenocarcinoma, resembling what is seen in the human disease (Xin et al 2006).…”

Androgen Receptor Promotes the Oncogenic Function of Overexpressed Jagged1 in Prostate Cancer by Enhancing Cyclin B1 Expression via Akt Phosphorylation

“…AR has been shown in prostate cancer epithelial cells to influence the expression levels and activities of several cell-cycle genes essential for the G 1 -S and G 2 -M cell-cycle transition (40,47). In addition, Akt regulates the expression and stability of AR at multiple levels, ranging from transcriptional to posttranslational modulation (48). We, therefore, hypothesized that AR and p-Akt may regulate the expression of cyclin B1 together.…”