The sphingolipid ceramide promotes cell cycle arrest, differentiation, senescence, and death. The mechanisms by which it affects these cellular processes are poorly defined. My lab has recently published data supporting a new model for ceramide action: starving cells to death. We found that ceramide generation results in rapid and profound nutrient transporter down-regulation in mammalian cells similar to what has been observed in yeast. To respond to this intracellular nutrient limitation, ceramide-exposed cells engage in protective autophagy, a starvation response by which cells digest their constituent molecules to obtain energy and essential nutrients. In further support of this bioenergetic model for ceramide action, supplying cells with a transporter-independent, cell-permeable nutrient, methyl pyruvate, blocked ceramide-induced death. Furthermore, inducing metabolic quiescence by gradually adapting cells to tolerate low extracellular nutrient levels completely eliminated ceramide toxicity. We propose to extend these studies through the following Specific Aims: 1) Identify the molecular pathways between ceramide and nutrient transporter proteins. The mechanisms by which ceramide causes nutrient transporter loss are undefined. We will determine the trafficking step affected by ceramide and whether several established ceramide effector proteins contribute to transporter loss. 2) Determine the mechanism of action for the anti-neoplastic dose of the sphingolipid analog, FTY720. We will determine whether FTY720 kills cells by down-regulating nutrient transporter proteins. We will also test our hypothesis that FTY720 has secondary effects on endocytic trafficking that increase its toxicity. These studies will allow us to refine our bioenergetic model for ceramide action and increase our understanding of how endocytic traffic is regulated. Studies with FTY720 may also serve as proof of the principle that targeting nutrient transporter proteins is a safe and effective therapeutic approach. Ceramide- induced nutrient transporter down-regulation may play an important role in the pathogenesis of cancer and type 2 diabetes. If so, these studies may also identify novel chemotherapeutic targets to treat these prevalent human diseases.

Public Health Relevance

The proposed studies are of broad medical relevance as ceramide plays a key role in many human diseases as well as in aging. The planned studies have particular relevance to cancer and type 2 diabetes and may lead to new therapeutic approaches to these prevalent diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Chin, Jean
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Irvine
Anatomy/Cell Biology
Schools of Arts and Sciences
United States
Zip Code
Garsi, Jean-Baptiste; Sernissi, Lorenzo; Vece, Vito et al. (2018) In search of constrained FTY720 and phytosphingosine analogs as dual acting anticancer agents targeting metabolic and epigenetic pathways. Eur J Med Chem 159:217-242
Finicle, Brendan T; Ramirez, Manuel U; Liu, Gang et al. (2018) Sphingolipids inhibit endosomal recycling of nutrient transporters by inactivating ARF6. J Cell Sci 131:
Kim, Seong M; Nguyen, Tricia T; Ravi, Archna et al. (2018) PTEN Deficiency and AMPK Activation Promote Nutrient Scavenging and Anabolism in Prostate Cancer Cells. Cancer Discov 8:866-883
McCracken, A N; McMonigle, R J; Tessier, J et al. (2017) Phosphorylation of a constrained azacyclic FTY720 analog enhances anti-leukemic activity without inducing S1P receptor activation. Leukemia 31:669-677
Selwan, Elizabeth M; Edinger, Aimee L (2017) Branched chain amino acid metabolism and cancer: the importance of keeping things in context. Transl Cancer Res 6:S578-S584
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Jaber, Nadia; Mohd-Naim, Noor; Wang, Ziqing et al. (2016) Vps34 regulates Rab7 and late endocytic trafficking through recruitment of the GTPase-activating protein Armus. J Cell Sci 129:4424-4435
Perryman, Michael S; Tessier, Jérémie; Wiher, Timothy et al. (2016) Effects of stereochemistry, saturation, and hydrocarbon chain length on the ability of synthetic constrained azacyclic sphingolipids to trigger nutrient transporter down-regulation, vacuolation, and cell death. Bioorg Med Chem 24:4390-4397
Kim, Seong M; Roy, Saurabh G; Chen, Bin et al. (2016) Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways. J Clin Invest 126:4088-4102
Selwan, Elizabeth M; Finicle, Brendan T; Kim, Seong M et al. (2016) Attacking the supply wagons to starve cancer cells to death. FEBS Lett 590:885-907

Showing the most recent 10 out of 21 publications