Many forms of cellular stress, including inflammatory cytokines and cancer chemotherapeutics, cause ceramide accumulation. Although disruptions in sphingolipid metabolism are associated with numerous diseases, how ceramide controls cell survival, proliferation, and differentiation is incompletely understood. Recently, it has been shown that ceramide and related sphingolipids trigger amino acid and glucose transporter internalization producing bioenergetic stress that leads to quiescence in normal cells and cell death in constitutively anabolic cancer cells. Whether sphingolipid treatment induces nutrient transporter loss through changes in transporter synthesis, degradation, internalization, or recycling is not yet known. This study will investigate the molecular mechanisms behind sphingolipid-induced nutrient transporter loss and determine the role they play in sphingolipid-induced cell death with implications for the development of new therapeutic approaches.
Aim 1 will test the hypothesis that sphingolipids increase nutrient transporter internalization and decrease recycling without affecting their degradation or synthesis.
Aim 2 will assess the relationship between Arf6 inactivation by sphingolipids and nutrient transporter loss and cell death.
Aim 3 will evaluate whether an inhibitor of Arf6, SecinH3, and sphingolipid analogs synergistically kill cancer cells, how broadly active this combination is, and whether normal cells are more resistant than transformed cells to this combination. Successful completion of these Aims will clarify the mechanisms by which sphingolipids modulate cell growth and survival. This work will also provide insight into the pathogenesis of conditions where sphingolipid metabolism is disrupted such as cancer, diabetes, and heart disease, and may suggest novel approaches to therapy and avoiding drug resistance.

Public Health Relevance

Sphingolipids regulate whole body metabolism and are involved in numerous human diseases. Understanding how sphingolipids control cellular growth and survival may give insight to the pathogenesis of metabolic diseases such as obesity, diabetes and cancer and could lead to the development of novel therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31GM106702-01A1
Application #
8838497
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Barski, Oleg
Project Start
2015-02-05
Project End
2017-02-04
Budget Start
2015-02-05
Budget End
2016-02-04
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
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: