Abstract 1968: Activation of AKT negatively regulates the pro-apoptotic function of death-associated protein kinase 3 (DAPK3) in prostate cancer

Autor: Sandhya R. Rao, Arokya Ms Papu John, Houda Alatassi, Ram Vinod Roy, Chendil Damodaran, Trinath P. Das, Murali M. Ankhem
Rok vydání: 2015
Předmět:
Zdroj: Cancer Research. 75:1968-1968
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.am2015-1968
Popis: Activation of AKT plays a central role by inducing pro-survival signaling pathways, promotes cell growth and inhibits apoptosis in human malignancies including prostate cancer. Higher expression of pAKT is correlated with aggressiveness of the prostate cancer. Published evidences suggest that inhibition of survival kinases may utilize the current therapeutic modalities to sensitize the prostate cancer cells more significantly. Indeed, numbers of small molecules or peptides are being developed to inhibit either AKT or its upstream kinase PI3K to inhibit the growth of human malignances. Death-associated protein kinase 3 (DAPK3), a serine/threonine kinase governs many signaling pathways including induction of apoptosis. This lead the way to focus our research on small molecules which can inhibit AKT activation and induce DAPK mediated apoptosis in CaP cell lines. To begin with, we identified a small molecule which binds to AKT kinase domain with a predicted affinity of ∼11.0 Kcal/mol. The amino acid residues of AKT-1 within 4 Å of the best docking site of this small molecule, 6-dimethyl, dihydro pyranone (6ddp), includes ARG-4, SER-7, LEU-156, GLY-157, LYS-158, GLY-159, PHE-161, VAL-164, LYS -179, GLU-191, HIS-194, GLU-234, ASP-274, MET-281, ASP-292, GLY-294,LEU-295, and PHE-438. The hydroxyl group of 6ddp likely forms a hydrogen bond with the nitrogen on the side chain of HIS-194. 6ddp inhibited pAKT (ser473) expression which concomitantly induced DAPK1 expression resulting in the growth inhibition of CaP cell lines. Similar results were obtained when a pharmacological inhibitor of AKT was used which resulted in DAPK induced apoptosis of CaP cells. Subsequently, we examined the DAPK3 activation in prostate cancer samples, which significantly showed a higher expression in normal prostate samples. On the contrary, reduced expression with low level was observed with the progression of disease. Currently, our study focuses on the kinase and phosphatase interaction network by mass spectrometric analysis of protein complexes. Understanding the mechanism of DAPK3 mediated AKT inhibition, may strengthen the therapeutic window for prostate cancer without causing much or any toxicity Citation Format: Trinath P. Das, Arokya MS Papu John, Ram V. Roy, Sandhya R. Rao, Houda Alatassi, Chendil Damodaran, Murali M. Ankhem. Activation of AKT negatively regulates the pro-apoptotic function of death-associated protein kinase 3 (DAPK3) in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1968. doi:10.1158/1538-7445.AM2015-1968
Databáze: OpenAIRE
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