Nutrient transporter regulation: A means to starve cancer cells to death

• Main Author: Rosales, Kimberly Romero
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2010
• Subjects: Cellular biology
• ISBN: 9781124208794; 1124208798

The molecular mechanisms that regulate nutrient transporter expression are poorly understood. Cells take in nutrients they require for growth and proliferation through nutrient transporters on their surface. Nutrient transporter expression is limited by growth factor availability. When cell growth exceeds homeostatic limits, growth factors become limiting inducing nutrient transporter down-regulation and a starvation-like phenotype. We studied three pathways that regulate nutrient transporter expression: 1) Rab7, a small GTPase involved in late endosome to lysosome fusion events, is required for nutrient transporter down-regulation following growth factor withdrawal 2) The sphingolipid ceramide shown to regulate nutrient permease expression in yeast and 3) The sphingosine analog FTY720, shown to have anti-cancer properties and also regulate nutrient permeases in yeast. We found that that Rab7 is activated by growth factor withdrawal allowing Rab7 to mediate nutrient transporter degradation in the lysosome. We also found that ceramide and FTY720 treatment induce rapid nutrient transporter down-regulation and cell death. Treatment with cell permeable nutrients reversed ceramide and FTY720 induced cell death, suggesting that these cells were starving to death. This loss of nutrient intake induced protective autophagy. Inhibition of autophagy sensitized cells to ceramide and FTY720. We hypothesized that cancer cells would be more sensitive to nutrient restriction than normal cells because oncogenic mutations force biosynthesis and cell division even when nutrient supplies are limited leading to a bioenergetic crisis. We found that slowing cellular metabolism using nutrient and growth factor adaptation, rapamycin and 2-DG treatment made cells resistant to nutrient transporter induced cell death. FTY720 was able to decrease leukemic burden and down-regulate nutrient transporters in BCR/ABL leukemic mouse model. Nutrient transporter down-regulation allows specific targeting of cancer cells based on their anabolic metabolism. Together our data suggests that targeting nutrient transporter proteins may be an effective chemotherapeutic strategy.