This proposal is designed to test our novel hypothesis that cellular stress-mediated acid ceramidase (AC) activation, invoked by radiation or chemotherapy, leads to resistance to apoptosis by induction of S1P-S1PR2- mediated AKT activation, leading to nuclear PTEN export. As a corollary, we also hypothesize that targeting AC inhibits S1P/AKT signaling, overcoming cell death resistance in the treatment of prostate cancer. We plan to dissect mechanisms of resistance at the molecular and pharmacological level to develop novel treatment strategies as follows:
Specific Aim 1. Determine the mechanisms of AC-dependent resistance to cell death following therapy stress.
Specific Aim 2. Determine the therapeutic roles of targeting the AC/SK1/S1P/AKT axis to overcome therapy resistance for the treatment of prostate cancer. Data obtained from these studies will provide novel mechanism-based therapeutic strategies to overcome resistance by targeting AC and/or SK/S1P signaling in solid tumors, including prostate, kidney/bladder and/or liver tumors, which are within the focus of this Program Project.
Studies proposed in this Project will help determine the mechanisms by which targeting the acid ceramidase (AC) and sphingosine 1-phosphate (S1P) signaling axis provides a novel therapeutic approach to overcome therapy resistance, leading to the prevention of relapse in solid tumors, such as prostate, urinary and liver cancers.
|Panneer Selvam, Shanmugam; Roth, Braden M; Nganga, Rose et al. (2018) Balance between senescence and apoptosis is regulated by telomere damage-induced association between p16 and caspase-3. J Biol Chem 293:9784-9800|
|Chatterjee, Shilpak; Chakraborty, Paramita; Daenthanasanmak, Anusara et al. (2018) Targeting PIM Kinase with PD1 inhibition Improves Immunotherapeutic Antitumor T-cell Response. Clin Cancer Res :|
|Schrecengost, Randy S; Green, Cecelia L; Zhuang, Yan et al. (2018) In Vitro and In Vivo Antitumor and Anti-Inflammatory Capabilities of the Novel GSK3 and CDK9 Inhibitor ABC1183. J Pharmacol Exp Ther 365:107-116|
|Ogretmen, Besim (2018) Sphingolipid metabolism in cancer signalling and therapy. Nat Rev Cancer 18:33-50|
|Helke, Kristi; Angel, Peggi; Lu, Ping et al. (2018) Ceramide Synthase 6 Deficiency Enhances Inflammation in the DSS model of Colitis. Sci Rep 8:1627|
|Chatterjee, Shilpak; Daenthanasanmak, Anusara; Chakraborty, Paramita et al. (2018) CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response. Cell Metab 27:85-100.e8|
|Britten, Carolyn D; Garrett-Mayer, Elizabeth; Chin, Steven H et al. (2017) A Phase I Study of ABC294640, a First-in-Class Sphingosine Kinase-2 Inhibitor, in Patients with Advanced Solid Tumors. Clin Cancer Res 23:4642-4650|
|Lv, Zongyang; Rickman, Kimberly A; Yuan, Lingmin et al. (2017) S. pombe Uba1-Ubc15 Structure Reveals a Novel Regulatory Mechanism of Ubiquitin E2 Activity. Mol Cell 65:699-714.e6|
|Thomas, Raquela J; Oleinik, Natalia; Panneer Selvam, Shanmugam et al. (2017) HPV/E7 induces chemotherapy-mediated tumor suppression by ceramide-dependent mitophagy. EMBO Mol Med 9:1030-1051|
|Scheffel, Matthew J; Helke, Kristi; Lu, Ping et al. (2017) Adoptive Transfer of Ceramide Synthase 6 Deficient Splenocytes Reduces the Development of Colitis. Sci Rep 7:15552|
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