Prostate cancer is the most frequently diagnosed male malignancy. The normal prostate development and prostate cancer progression are mediated by androgen receptor (AR). Recently, the roles of cyclin-dependent kinase 5 (Cdk5) and its activator, p35, in cancer biology are explored one after another. We have previously demonstrated that Cdk5 may regulate proliferation of thyroid cancer cells. In addition, we also identify that Cdk5 overactivation can be triggered by drug treatments and leads to apoptosis of prostate cancer cells. The aim of this study is to investigate how Cdk5 regulates AR activation and growth of prostate cancer cells. At first, the data show that Cdk5 enables phosphorylation of AR at Ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of AR proteins. The Cdk5-dependent AR stabilization causes accumulation of AR proteins and subsequent activation. Besides, the positive regulations of Cdk5-AR on cell growth are also determined in vitro and in vivo. S81A mutant of AR diminishes its interaction with Cdk5, reduces its nuclear localization, fails to stabilize its protein level, and therefore, decreases prostate cancer cell proliferation. Prostate carcinoma specimens collected from 177 AR-positive patients indicate the significant correlations between the protein levels of AR and Cdk5 or p35. These findings demonstrate that Cdk5 is an important modulator of AR and contributes to prostate cancer growth. Therefore, Cdk5-p35 may be suggested as diagnostic and therapeutic targets for prostate cancer in the near future.Prostate cancer is a commonly diagnosed malignancy in men, and androgen plays an important role in its early development (1). Androgen deprivation has been considered as a common therapy for androgen-dependent prostate cancer. However, the existing cancer cells eventually become hormone-refractory, and the following therapy usually gets into scrapes. The androgen receptor (AR), 2 which belongs to the steroid receptor family and plays pivotal roles in the development of the prostate gland and the pathogenic progression of prostate cancer. High levels of AR expression along with its target genes have been reported in hormone-refractory prostate cancer cells, suggesting that AR signaling is activated regardless of the levels of serum androgen (2). A study analyzing consensus sequences of phosphorylation indicates that AR contains more than 40 predicted phosphorylation sites (3). Ser-81 of the AR N terminus is the most intensely phosphorylated site in response to androgen binding (4). The latest report reveals the relevance of Ser-81 phosphorylation and AR promoter selectivity as well as cell growth (5). Our recent work also shows the increase of Ser-81 phosphorylation of AR in the androgen-independent LNCaP sub-line (6). Fu et al. (7) proposed that the phosphorylation consensus sequence (SPRT) of cyclin-dependent kinase 5 (Cdk5) corresponds with the sequence around AR Ser-81. Although AR was reported as substrates for Cdk9 (5) as well as Cdk1 (8), whi...
Cyclin-dependent kinase 5 (Cdk5) is known to regulate prostate cancer metastasis. Our previous results indicated that Cdk5 activates androgen receptor (AR) and supports prostate cancer growth. We also found that STAT3 is a target of Cdk5 in promoting thyroid cancer cell growth, whereas STAT3 may play a role as a regulator to AR activation under cytokine control. In this study, we investigated the regulation of Cdk5 and its activator p35 on STAT3/AR signaling in prostate cancer cells. Our results show that Cdk5 biochemically interacts with STAT3 and that this interaction depends on Cdk5 activation in prostate cancer cells. (20). Androgen ablation therapy is the primary strategy for suppressing prostate cancer growth; however, some castration-resistant prostate cancers eventually relapse within two years. Therefore, it is imperative to further understand the molecular mechanisms of prostate cancer progression and to develop effective treatment strategies.Signal transducer and activator of transcription 3 (STAT3), a transcription factor, has been reported to regulate prostate cancer development (4, 16). It has been suggested that the transcriptional activity of STAT3 is initiated by phosphorylation at tyrosine 705 (Tyr Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase. Without participating in cell cycle progression, Cdk5 has been implicated in various aspects of neural functions (11). Distinct from the other Cdk family members, Cdk5 is activated not by binding to cyclins but rather through association with its regulatory subunits p35 and p39 (37, 38). p35 (Cdk5R1), a 35-kDa protein, has been widely investigated and was originally defined as a neuron-specific activator of Cdk5 (38). Recently, p35 was indicated to play important roles in human cancers by regulating Cdk5 activity (15,26,27,36), and p35 overexpression was also reported in metastatic prostate cancers (36). Multiple functions of Cdk5 in addition to those in the central nervous system were recently discovered, such as its roles in cancer biology (6,22,26,27,36). In our previous research, we first identified the kinase activity and apoptotic role of Cdk5 in prostate cancer cells (27). Our recent work demonstrates the modulation of prostate cancer growth by Cdk5 through activation of androgen receptor (AR) by phosphorylation (15). Several lines of evidence have revealed that STAT3 can be modulated by Cdk5-dependent phosphorylation at the Ser 727 site in mouse neurons (12), muscle cells (12), and liver cancer (34). A recent study indicates that Cdk5 prevents DNA damage through Ser 727 phosphorylation of STAT3 (9). Our previous results also show that Cdk5 modulates STAT3 activation and cell proliferation of thyroid cancer (26).STAT3 has been shown to modulate signaling cross-talk between steroid receptors such as AR (39) or glucocorticoid receptor (47) and other signaling pathways in response to
Cdk5 is a small serine/threonine protein kinase which belongs to Cdk family. Unlike other Cdk members. so far Cdk5 is known to be irrelevant in cell cycle. Cdk5 kinase activity is regulated by binding with its activator, p35. Our previous results indicate that Cdk5 and p35 are involved in drugs-induced apoptosis of prostate cancer cells. Retinoic acid (RA) is one of the vitamin A-related compounds. Because of its potency on biological functions, it has been widely studied in its novel actions including the ability to inhibit cancer cell growth and to induce apoptosis. Here, we report that RA treatment decreased the growth of human cervical cancer cell line, HeLa, and Cdk5 contributed to this effect. The involvement of Cdk5 in RA-reduced cell survival was performed by treatments of Cdk5 inhibitor and siRNA. We further identified that RA-induced growth inhibition was partly correlated to Cdk5 activity-related apoptosis by detecting cell cycle distribution of sub G1 phase and the signals of Annexin V staining. In addition, our results also indicated that Cdk5 activity was involved in RA-induced HeLa apoptosis by detecting cleavages of caspase-3 and its substrate, PARP (poly (ADP-ribose) polymerases). Interestingly, the nuclear localizations of Cdk5 and p35 proteins were increased by RA treatment, which, again, suggests the involvement of Cdk5 and p35 in RA-induced apoptotic effects. In conclusion, we provide evidence to suggest that Cdk5 and p35 might play important roles in RA-induced HeLa apoptosis
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