A Novel Nuclear Interaction Between Androgen Receptor and TM4SF3
Abstract
Androgen acts in prostate cancer, as in normal development, by binding to and activating the androgen receptor (AR). Because of the importance of AR in prostate cancer, several drugs have been developed targeting activation of this protein. These drugs either block androgen production or androgen binding to the AR. While these treatments can be effective against primary prostate cancer, they fail against recurrent disease, which is known as castration-resistant prostate cancer (CRPC). Indeed, more recently developed drugs specifically for CRPC, such as enzalutamide, only offer patients just a few months of additional survival. Thus, new, more effective treatments are needed. Our lab has recently discovered a new regulator of the AR protein, the TM4SF3 protein. This finding is interesting on several important levels. First, TM4SF3 is protein found on the membrane of cells and represents the first example of AR interacting with a membrane protein. Secondly, our data show that TM4SF3 and AR interact directly with one another. Thirdly, TM4SF3 regulation of AR protein affects AR activity in prostate cancer cells. Finally, most importantly, AR and TM4SF3 form a protein complex in the nucleus of prostate cancer cells that blocks the degradation of both proteins. Thus, when TM4SF3 associates with AR, it stabilizes the AR protein and itself, providing cancer cells an enhanced ability to survive, grow, and undergo metastasis, three steps that are essential for CRPC to develop. Our data also show that TM4SF3 protein levels are higher in prostate cancer tissue than normal prostate and the highest in advanced prostate cancer. These data also show a strong correlation in expression of AR and TM4SF3 proteins in prostate cancer. All these data argue that TM4SF3 is an important regulator of AR activity in prostate cancer and thus warrants further studies. Thus, we want to study the AR/TM4SF3 interaction in prostate cancer cells and in animal tumor models so that we better understand how AR and TM4SF3 interact and how common this interaction is in prostate tumors, and how important it is in prostate cancer development using a mouse model. Having this information can allow us to develop ways to disrupt this AR/TM4SF3 interaction and thus cause both proteins to be degraded, which will drive cancer cells to die. Since this interaction is also found in cultured cells that mimic CRPC, then it is possible for this proposed work to lead to new therapies against CRPC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710263
Entities
People
- Lirim Shemshedini
Organizations
- United States Army
- University of Toledo