Resistance to the androgen-deprivation therapy (ADT) is the major cause of prostate cancer (PCa)- related death. Mechanisms underlying the ADT resistance are not well understood and the strategies for overcoming the resistance have not been well developed, which will be addressed innovatively in this proposal. YAP and TAZ are transcription co-activators and form complexes with transcription factors including TEAD1-4 to regulate expression of their target genes that control cell proliferation, apoptosis, and tumorigenesis. Little is known about the effects of YAP and TAZ and the YAP/TAZ target genes on the ADT responses and the PCa progression. We demonstrate originally in this proposal that TAZ level and activity are higher in the androgen-insensitive compared to the androgen- sensitive PCa cells and that the ADT up-regulates the level and activity of TAZ, Levels of AXL receptor tyrosine kinase (RTK) and angiopoietin-1 (Angpt1), a ligand of Tie2 RTK. In addition, knockdown of TAZ but not YAP sensitizes the PCa cell response to the ADT and a constitutively active (CA) TAZ mutant, TAZ-S89A, confers the ADT resistance whereas an AXL inhibitor and the Angpt1-Tie2 inhibitors sensitize the ADT response of PCa cells. Furthermore, we show that TAZ up- regulates Angpt1 and ADAM 8 expression and that Angpt1 promotes Tie2 activation and ADAM8 promotes AXL cleavage/shedding, resulting in the ligand-independent AXL activation. We will test a novel hypothesis that TAZ plays a key role in promoting the ADT resistance of PCa and that TAZ induces the ADT resistance by up-regulating and activating AXL in the TEAD2/4 and ADAM8 dependent manner, respectively; and by enhancing activity of the Angpt1-Tie2 functional axis through up-regulating Angpt1. We further hypothesize that inhibition of TAZ activity and/or combinational inhibition of the AXL shedding/activity and the Angpt1-Tie2 activity are novel approaches for sensitizing the ADT response of PCa and blocking the PCa progression.
Three specific aims are proposed.
Aim 1 is to establish that TAZ promotes the ADT resistance through or partially through AXL.
Aim 2 is to determine the contribution of the Angpt1-Tie2 functional axis to the TAZ-induced ADT resistance.
Aim 3 is to establish that inhibition of TAZ activity and combinational inhibition of the Angpt1-Tie2 activity and the AXL shedding/activity are novel approaches to overcome the ADT resistance of PCa. Results obtained will establish that TAZ and the TAZ effectors, AXL, ADAM8, and Angpt1, are the novel molecular determinants underlying the ADT resistance and they serve as novel therapeutic targets. Furthermore, accomplishment of this proposal will lead to development of the novel inhibitors of TAZ, AXL/ADMA8, and Angpt1/Tie2 activities and the novel combinations of these inhibitors to sensitize the ADT response of PCa. Therefore, this proposal is highly significant.
Resistance to the androgen-deprivation therapy (ADT) is the major cause of prostate cancer (PCa)-related death. This proposal aims to identify the novel mechanisms underlying the TAZ/ADAM8/AXL- and TAZ/Angpt1- Tie2-mediated ADT resistance; establish TAZ, ADAM8, AXL, and Angpt1-Tie2 as novel therapeutic targets for sensitizing the PCa response to the ADT; and develop the efficacious inhibitors of TAZ, ADAM8/AXL, and Angpt1/Tie2 and their novel combinations against the ADT resistance of PCa. Therefore, this proposal is of high biologic and clinical relevance and therapeutic and translational potentials, and is highly significant.
| Xu, Yin; Wang, Kaiqiang; Yu, Qin (2016) FRMD6 inhibits human glioblastoma growth and progression by negatively regulating activity of receptor tyrosine kinases. Oncotarget 7:70080-70091 |
