Cyclin-dependent kinase 5 modulates STAT3 and androgen receptor activation through phosphorylation of Ser⁷²⁷ on STAT3 in prostate cancer cells

Abstract

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

All-Trans Retinoic Acid Induces DU145 Cell Cycle Arrest through Cdk5 Activation

“…Subsequently, we found that the abnormal activation of Cdk5 triggered by intracellular calcium increase is involved in the apoptosis of prostate cancer cells [22]. Recently, our data also showed that a physiological activation of Cdk5 can phosphorylate and stimulate the androgen receptor and STAT3 and the growth of prostate cancer is therefore regulated [13,23]. Brown et al also indicate that ATRA-induced cell differentiation is correlated with the change in intracellular calcium [24].…”

Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its Nuclear Accumulation Suppresses Gastric Tumorigenesis

“…It has also been documented that different CDKs may contribute specifically to different tumor types in humans (17,18). CDK5, an atypical CDK that was previously considered to function in processes unrelated to cell-cycle regulation, has been shown to play a fundamental role in several kinds of carcinomas including breast, lung, prostate, multiple myeloma, and pancreatic cancers (39)(40)(41)(42)(43). However, the potential role of CDK5 in gastric cancer has never been reported.…”

“…This may suggest that CDK5 in fact plays an inhibitory role in gastric tumorigenesis. The kinase activity of CDK5 has been thought to mediate carcinogensis of certain nongastric cancer types (39)(40)(41)(42)(43). Our previous studies indicated that nuclear CDK5 can function as a cell-cycle suppressor in the nervous system (28)(29)(30).…”

The Emerging Role of Cdk5 in Cancer

“…In normal cells, STAT3 becomes activated following cell stimulation by a cytokine or growth factor, while in cancer cells STAT3 is often deregulated. Cdk5 interacts with and phosphorylates STAT3 at Ser-727, which is necessary for MTC and prostate cancer cells proliferation [27, 28]. STAT3-target genes are indeed induced upon Cdk5 activation.…”

“…STAT3-target genes are indeed induced upon Cdk5 activation. Importantly, prostate cancer cells and prostate cancer patient tumors express Cdk5, p35 and phosphorylated Ser-727 STAT3 [28, 29]. It would be interesting to define the determinants for Cdk5-dependent phosphorylation of Rb versus STAT3.…”