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ASC-J9® suppresses prostate cancer cell invasion via altering the sumoylation-phosphorylation of STAT3
WanYing Lin1, Jie Luo1, Yin Sun1
1George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
Abstract:
The androgen-deprivation therapy (ADT) to either reduce the androgen biosynthesis (for example, Abiraterone) or to prevent binding of androgen to the androgen receptor (AR), for example using Casodex or Enzalutamide, which may result in .decrease of the prostate cancer (PCa) cell growth, yet may also increase the PCa cell invasion. In contrast, the recently identified AR degradation enhancer ASC-J9® may function via degrading the AR protein to simultaneously suppress the PCa cell proliferation and invasion. The details of this unique mechanism, however, remain unclear. Here we found that ASC-J9® could suppress PCa cell invasion via inducing the sumoylation of STAT3, thereby inhibiting the STAT3 phosphorylation that led to suppress the EMT-SNAIL2 signals in both PCa DU145 and PC3 AR-negative cells. Mutation of lysine-679 on the sumoylation site of the STAT3 effectively blocked the ASC-J9®-suppressed PCa cell invasion in both in vitro cell lines and in vivo mouse models. These results suggest that in addition to degrading AR to suppress PCa cell proliferation, ASC-J9® can also function through an AR-independent mechanism via modulating the STAT3 sumoylation to alter the phospho-STAT3 status to suppress the PCa cell invasion. These dual functions of ASC-J9® to suppress PCa proliferation and invasion (via altering STAT3 sumoylation) may help us to develop a better anti-AR compound that may overcome the current antiandrogens' unwanted side-effect of increasing the metastasis to better suppress the castration-resistant PCa progression.
Insights
Androgen-deprivation therapy (ADT) for prostate cancer (PCa) can increase cell invasion. ASC-J9® suppresses PCa invasion by inducing STAT3 sumoylation, offering a potential new therapy to overcome ADT side effects.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Androgen-deprivation therapy (ADT) is a standard prostate cancer (PCa) treatment that reduces tumor growth but can paradoxically increase cell invasion.
- Current ADT drugs like Abiraterone, Casodex, and Enzalutamide target androgen biosynthesis or androgen receptor (AR) binding.
- The AR degradation enhancer ASC-J9® shows potential for simultaneously suppressing PCa proliferation and invasion, but its mechanism is not fully understood.
Purpose of the Study:
- To elucidate the mechanism by which ASC-J9® suppresses PCa cell invasion.
- To investigate the role of STAT3 sumoylation in ASC-J9®'s anti-invasive effects.
- To explore the potential of ASC-J9® as a novel therapeutic agent for castration-resistant PCa.
Main Methods:
- Investigated ASC-J9®'s effect on PCa cell invasion in vitro (DU145 and PC3 cell lines).
- Analyzed the role of STAT3 sumoylation and phosphorylation in response to ASC-J9® treatment.
- Utilized site-directed mutagenesis (K679R) to assess the importance of STAT3 sumoylation.
- Validated findings in vivo using mouse models.
Main Results:
- ASC-J9® suppressed PCa cell invasion by inducing STAT3 sumoylation, which inhibited STAT3 phosphorylation.
- This inhibition of phospho-STAT3 led to the suppression of epithelial-mesenchymal transition (EMT)-SNAIL2 signaling.
- Mutation of the STAT3 sumoylation site (Lysine-679) blocked ASC-J9®'s anti-invasive effects in vitro and in vivo.
- ASC-J9® demonstrated an AR-independent mechanism for suppressing invasion.
Conclusions:
- ASC-J9® suppresses PCa cell invasion through an AR-independent pathway involving STAT3 sumoylation and subsequent inhibition of STAT3 phosphorylation.
- This mechanism effectively reduces EMT-SNAIL2 signaling, a key driver of cancer cell invasion and metastasis.
- ASC-J9®'s dual action—suppressing proliferation via AR degradation and invasion via STAT3 modulation—offers a promising therapeutic strategy to overcome the limitations of current ADT and combat castration-resistant PCa progression.
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