Our long-term goal is to define the mechanisms by which anti-cancer chemotherapeutic agents (ACCAs) induce anti-proliferative responses (proliferation inhibition and programmed cell death) in tumor cells by focusing on human alkaline ceramidase 2 (ACER2) and its lipid substrate (ceramide) and product (sphingosine). Many ACCAs induce the generation of the bioactive sphingolipid ceramide in tumor cells, and blocking ceramide generation inhibits anti-proliferative effects of the drugs, suggesting that ceramide is an important mediator of ACCAs in this anti-proliferative response. Ceramide can be hydrolyzed into sphingosine by ceramidases in human cells and, like ceramide, SPH can potently induce anti-proliferative effects in tumor cells both in vitro and in animal models. Increasing expression of neutral ceramidase ASAH2 on the plasma membrane also attenuates cell apoptosis induced by TNF-1, a known ceramide-generating cytokine. In contrast, our preliminary studies show that increasing the conversion of ceramide to SPH by the Golgi alkaline ceramidase 2 (ACER2) markedly enhances the cytotoxicity of doxorubicin, a known ceramide-inducing ACCA, in HeLa cells, whereas knocking down ACER2 has the opposite effect. This exciting finding led us to the hypotheses that ACCAs exert anti-proliferative responses in cancer cells through the ceramide/ACER2/SPH pathway and that activation of this pathway will augment chemotherapy action in cancer treatment. To test this hypothesis, we will establish that the ceramide/ACER2/SPH pathway is an important mediator of the anti- proliferative responses of ACCAs in cancer cells by determining 1) if ACCAs induce the anti-proliferative responses in cancer cells by activating the ceramide/ACER2/SPH pathway;2) if ACER2-inducing agents enhance whereas ACER2-inhibiting agents attenuate the ACCA-induced anti-proliferative effects in cancer cells (Aim 1).
In Aim 2, we will test the hypothesis that its Golgi localization is required for ACER2 to mediate the ACCA-induced anti-proliferative responses in cancer cells by investigating 1) if targeting ACER2 to the endoplasmic reticulum (ER) abolishes its ability to mediate the ACCA-induced anti-proliferative effects in tumor cells;and 2) if targeting ASAH2 to the Golgi complex confers the ability to mediate ACCA-induced anti- proliferative effects in tumor cells.
For Aim 3, we will test the hypothesis that the activation of the ACER2/SPH pathway enhances anti-proliferative responses of ACCAs in tumor cells through Golgi fragmentation. We will determine 1) if ACCAs induces Golgi fragmentation by activating the ceramide/ACER2/SPH pathway;2) if SPH induces Golgi fragmentation and inhibits Golgi reassembly in vitro;3) if activating the ceramide/ACER2/SPH inhibits Golgi assembly by inhibiting the stacking function of GRASP65 (Golgi reassembly stacking protein of 65 kD) and GRASP55;and 4) if activation of the ceramide/ACER2/SPH pathway induces mitotic arrest and apoptosis through Golgi fragmentation. These studies will provide insights into the role and mechanism of action of ACER2 and its product SPH in mediating anti-proliferative responses in cancer cells.
Approximately 1500 people die each day in the United States due to cancer. Therefore, better strategies for cancer treatment are necessary. PI's group and others have demonstrated that a group of lipids called sphingolipids, especially, ceramide and sphingosine (SPH), which are found in human cells, can potently kill tumor cells. The PI's group has identified a human enzyme called alkaline ceramidase 2 (ACER2) responsible for the generation of SPH from ceramide in tumor cells. The PI's group finds that increasing ACER2 expression substantially augments the efficacy of doxorubicin, a ceramide-inducing chemotherapeutic agent, in killing cancer cells by increasing the generation of SPH cancer cells. The PI's group is investigating whether and how increasing ACER2 expression also enhances the efficacy of other chemotherapeutic agents against cancer cells. Based on this study, the PI hopes to develop novel approaches for cancer treatment.
|Begum, Mahfuj A; Shi, Xiao-Xiao; Tan, Ye et al. (2016) Molecular Characterization of Rice OsLCB2a1 Gene and Functional Analysis of its Role in Insect Resistance. Front Plant Sci 7:1789|
|Xu, Ruijuan; Wang, Kai; Mileva, Izolda et al. (2016) Alkaline ceramidase 2 and its bioactive product sphingosine are novel regulators of the DNA damage response. Oncotarget 7:18440-57|
|Yi, Jae Kyo; Xu, Ruijuan; Jeong, Eunmi et al. (2016) Aging-related elevation of sphingoid bases shortens yeast chronological life span by compromising mitochondrial function. Oncotarget 7:21124-44|
|Edvardson, Simon; Yi, Jae Kyo; Jalas, Chaim et al. (2016) Deficiency of the alkaline ceramidase ACER3 manifests in early childhood by progressive leukodystrophy. J Med Genet 53:389-96|
|Wang, K; Xu, R; Snider, A J et al. (2016) Alkaline ceramidase 3 deficiency aggravates colitis and colitis-associated tumorigenesis in mice by hyperactivating the innate immune system. Cell Death Dis 7:e2124|
|Wang, Kai; Xu, Ruijuan; Schrandt, Jennifer et al. (2015) Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain. PLoS Genet 11:e1005591|
|Zhu, Congyi; Wang, Weili; Wang, Mingshuang et al. (2015) Deletion of PdMit1, a homolog of yeast Csg1, affects growth and Ca(2+) sensitivity of the fungus Penicillium digitatum, but does not alter virulence. Res Microbiol 166:143-52|
|Casasampere, Mireia; Camacho, Luz; Cingolani, Francesca et al. (2015) Activity of neutral and alkaline ceramidases on fluorogenic N-acylated coumarin-containing aminodiols. J Lipid Res 56:2019-28|
|HernÃ¡ndez-Corbacho, MarÃa JosÃ©; Canals, Daniel; Adada, Mohamad M et al. (2015) Tumor Necrosis Factor-Î± (TNFÎ±)-induced Ceramide Generation via Ceramide Synthases Regulates Loss of Focal Adhesion Kinase (FAK) and Programmed Cell Death. J Biol Chem 290:25356-73|
|Zhu, Congyi; Wang, Mingshuang; Wang, Weili et al. (2014) Glucosylceramides are required for mycelial growth and full virulence in Penicillium digitatum. Biochem Biophys Res Commun 455:165-71|
Showing the most recent 10 out of 12 publications