Cell Signaling and Cancer Therapy

Biography

Biography: Alexander Kazansky

Abstract

Prostate cancer remains one of the most common and potentially lethal neoplastic manifestations among men. In many cases, malignant transformation can be directly linked to activation of the STAT family of transcription factors. STAT5B, a specific member of the STAT family is intimately associated with prostate tumor progression. While the full form of STAT5B is thought to promote tumor progression, a naturally occurring truncated isoform acts as a tumor suppressor. We previously demonstrated that truncated STAT5 is generated by insertion of an alternatively spliced exon and results in the introduction of an early termination codon. In this report we demonstrate a new approach aimed at inhibition the expression of full-length STAT5B (a proto-oncogene) while simultaneously enhancing the expression of STAT5∆B (a tumor suppressor). The presented work combines the actions of steric-blocking splice-switching oligonucleotides (SSOs) and a novel nanotechnology-based approach for targeted delivery of DNA to tumor cells. We were able to block alternative splicing of STATs mRNA applying conjugates of SSO with pH insertion peptide (pHLIP). Our data demonstrates the functional effect of the intron/exon proportional tuning toward anti-cancer activity. A common feature of most STATs is alternative splicing, which leads to generation of a dominant-negative isoform. STAT proteins are involved in wide variety of physiological processes including immune response and tumor progression. Ability to modulate their actions and specifically switch function from tumor activating to tumor suppressing would be highly beneficial in many areas of biomedical research. In conclusion we developed and confirmed a novel method to implement steric-blocking splice-switching oligonucleotides for targeted delivery towards the development of novel therapeutic strategies.