Deciphering the Role of SLX4IP in Telomere Maintenance Mechanisms of Castrateresistant Prostate Cancer
Authors: Whited Tawna L , Taylor Derek J 
Published: June 2021

Androgen deprivation therapy persists as first‐line treatment for advanced prostate cancer despite the unescapable progression to castrate‐resistant prostate cancer (CRPCa). Castrate resistance is acquired through numerous mechanisms altering androgenic signaling, further complicating disease progression. Therapeutics have been developed for CRPCa; however, these provide limited benefit, as these agents remain targeted against the altered androgenic signaling environment exhibited by this disease. To address the limited treatment options available, it is essential to interrogate regulatory networks in CRPCa that function independent or downstream of androgenic signaling, ideally identifying fruitful therapeutic targets. Preliminary data suggests SLX4IP, a relatively uncharacterized protein involved in telomere maintenance mechanism (TMM) plasticity, may fulfill this therapeutic prerequisite. TMMs in malignancy are responsible for the elongation of telomeres at chromosomal ends to instill replicative immortality, with the two TMMs available being the telomerase pathway and the alternative lengthening of telomeres (ALT) pathway. It is well established that, if necessary, cancer cells have the ability to utilize the alternate pathway if the primary is disrupted to perpetuate replication. Additionally, the ALT pathway and elevated SLX4IP expression have been shown to correlate with aggressive phenotypes of CRPCa, specifically metastatic and neuroendocrine disease, both exhibiting bleak patient outcomes. To first determine if SLX4IP is capable of mediating TMM plasticity, SLX4IP was overexpressed in a telomerase‐positive cell line followed by TMM characterization. This analysis demonstrated a TMM switch occurred with the cells primarily utilizing the ALT pathway for telomere elongation. Conversely, SLX4IP knockdown in an ALT‐positive cell line initiated a transition to telomerase utilization. After establishing the critical role of SLX4IP in TMM plasticity, SLX4IP was overexpressed in CRPCa cell lines and proliferation rates were evaluated as a surrogate marker of aggressiveness in vitro. Elevated proliferation rates were identified in CRPCa cell lines utilizing ALT however, no significant change was noted in proliferation rates of telomerase‐positive cell lines overexpressing the protein. Taken together these data suggest that SLX4IP may govern the aggressive, ALT‐positive CRPCa phenotype however, additional studies are underway to further confirm this relationship. Ideally, these studies will determine the feasibility of modulating SLX4IP expression in CRPCa to promote telomerase utilization and less aggressive characteristics of the disease. Once the presumed less aggressive, telomerase‐positive phenotype is established, nucleoside analogs that elicit cytotoxicity via telomerase‐dependent misincorporation can then be utilized, providing additional treatment strategies for CRPCa.

Support or Funding Information

This work was supported in part by an NIH T32 (GM008803) grant.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.