The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer. However, the downstream translationally regulated nodes of gene expression that may direct cancer development are poorly characterized. Using ribosome profiling, we uncover specialized translation of the prostate cancer genome by oncogenic mTOR signalling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism and invasion. We extend these findings by functionally characterizing a class of translationally controlled pro-invasion messenger RNAs that we show direct prostate cancer invasion and metastasis downstream of oncogenic mTOR signalling. Furthermore, we develop a clinically relevant ATP site inhibitor of mTOR, INK128, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure. Together, these findings extend our understanding of how the ‘cancerous’ translation machinery steers specific cancer cell behaviours, including metastasis, and may be therapeutically targeted.
The human prostate gland is an important target organ of androgenic hormones. Testosterone and dihydrotestosterone interact with the androgen receptor to regulate vital aspects of prostate growth and function including cellular proliferation, differentiation, apoptosis, metabolism, and secretory activity. Our objective in this study was to characterize the temporal program of transcription that reflects the cellular response to androgens and to identify specific androgen-regulated genes (ARGs) or gene networks that participate in these responses. We used cDNA microarrays representing about 20,000 distinct human genes to profile androgen-responsive transcripts in the LNCaP adenocarcinoma cell line and identified 146 genes with transcript alterations more than 3-fold. Of these, 103 encode proteins with described functional roles, and 43 represent transcripts that have yet to be characterized. Temporal gene expression profiles grouped the ARGs into four distinct cohorts. Five uncharacterized ARGs demonstrated exclusive or high expression levels in the prostate relative to other tissues studied. A search of available DNA sequence upstream of 28 ARGs identified 25 with homology to the androgen responseelement consensus-binding motif. These results identify previously uncharacterized and unsuspected genes whose expression levels are directly or indirectly regulated by androgens; further, they provide a comprehensive temporal view of the transcriptional program of human androgen-responsive cells.T he androgenic hormones testosterone and dihydrotestosterone exert their cellular effects by means of interactions with the androgen receptor (AR), a member of the family of intracellular steroid hormone receptors that function as liganddependent transcription factors (1). Ligand-activated AR, complexed with coactivator proteins and general transcription factors, binds to cis-acting androgen response elements (AREs) located in the promoter regions of specific target genes and serves to activate or to repress transcription (1, 2). During human development, circulating androgens and a functional AR mediate a wide range of reversible and irreversible effects that include the morphogenesis and differentiation of major target tissues such as the prostate, seminal vesicles, and epididimus. The prostate gland has been used extensively as a model system to study androgen effects. In part, this is because of the fact that androgens promote the development and progression of prostate diseases that account for significant morbidity in the population including benign prostatic hypertrophy and prostate adenocarcinoma (2). The recognition that normal and neoplastic prostate epithelial cells depend on circulating androgens for their continued survival and growth led to the development of effective endocrine-based therapy for prostate carcinoma (3). To date, manipulating the androgen pathway by means of surgical or chemical castration remains the primary therapeutic modality for advanced prostate cancer.In the human prostate, the AR mediates ...
Normal prostatic epithelium depends on androgens for growth, development, secretory function, and survival (1-4). Most remarkably, androgen ablation induces massive apoptosis of prostatic epithelium (2, 5-8). Loss of androgen dependence occurs invariably during prostate carcinogenesis, accounting for poor long term success of androgen ablation therapy (9). Recent studies (10) show that acquisition of androgen autonomy occurs despite retention or elevated expression of the androgen receptor (AR) 1 in the majority of prostate tumors. AR, a 110-kDa zinc finger transcription factor belonging to the nuclear receptor superfamily, is activated by phosphorylation (11) and dimerization upon ligand binding. This promotes nuclear localization and binding of AR to androgenresponsive elements in the promoters of androgen-regulated genes. AR-mediated transcription is regulated by many ARinteracting proteins such as ARA 70 (AR-associated proteins) (12) and ARA 160 (13), along with cAMP-response element-binding protein (14), AP-1 (9, 15), and Ets (16). The growing list of recently discovered AR transcriptional co-regulators supports the notion that complex networks of signals tightly regulate transcription by androgens. Understanding how these signals promote growth and maintain cell viability will certainly impact on the therapeutic strategies for the prevention and cure of prostate cancer.TGF-, a potent regulator of cell growth, differentiation, apoptosis, and carcinogenesis in the prostate (17)(18)(19)(20), is under androgenic control. TGF- signals through a cooperative interaction with two cell surface serine/threonine kinase receptors, . TGF- first associates with constitutively active dimeric TRII, which then recruits and activates TRI kinase by transphosphorylation at a juxtamembrane glycine-serine repeat (21,26). With the help of Smad anchor for receptor activation (27), phosphorylated TRI is able to activate Smads 2 and 3 by phosphorylating their carboxyl-terminal serine-serine-Xaa-serine motifs (28). Active Smads 2 and 3 can form heteromeric complexes with co-Smad4, and either directly or through interactions with transcription factors and co-regulators bind to Smad-binding elements (SBEs) in TGF--regulated genes (29 -31). Further activation of Smads 2 and 3 is blocked by Smad7, whose expression is induced upon TGF- stimulation (32).Androgens negatively regulate TGF-1 ligand (17, 33) and receptor expression (34,35), along with Smad expression and activation (36) in the prostate. Recent reports show AR associates with Smad3 and that this association may either enhance
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