TY - JOUR
T1 - Nutrient transporters in cancer
T2 - Relevance to Warburg hypothesis and beyond
AU - Ganapathy, Vadivel
AU - Thangaraju, Muthusamy
AU - Prasad, Puttur D.
PY - 2009/1
Y1 - 2009/1
N2 - Tumor cells have an increased demand for nutrients; this demand is met by increased availability of nutrients through vasculogenesis and by enhanced cellular entry of nutrients through upregulation of specific transporters. This review focuses on three groups of nutrient transporters relevant to cancer: glucose transporters, lactate transporters, and amino acid transporters. Tumor cells enhance glucose uptake via induction of GLUT1 and SGLT1, and coordinate the increased entry of glucose with increased glycolysis. Since enhanced glycolysis in cancer is associated with lactate production, tumor cells must find a way to eliminate lactic acid to prevent cellular acidification. This is achieved by the upregulation of MCT4, a H+-coupled lactate transporter. In addition, the Na+-coupled lactate transporter SMCT1 is silenced in cancer. SMCT1 also transports butyrate and pyruvate, which are inhibitors of histone deacetylases. The silencing of SMCT1 occurs in cancers of a variety of tissues. Re-expression of SMCT1 in cancer cell lines leads to growth arrest and apoptosis in the presence of butyrate or pyruvate, suggesting that the transporter may function as a tumor suppressor. Tumor cells meet their amino acid demands by inducing xCT/4F2hc, LAT1/4F2hc, ASCT2, and ATB0,+. xCT/4F2hc is related primarily to glutathione status, protection against oxidative stress, and cell cycle progression, whereas the other three transporters are related to amino acid nutrition. Pharmacologic blockade of LAT1/4F2hc, xCT/4F2hc, or ATB0,+ leads to inhibition of cancer cell growth. Since tumor cells selectively regulate these nutrient transporters to support their rapid growth, these transporters have potential as drug targets for cancer therapy.
AB - Tumor cells have an increased demand for nutrients; this demand is met by increased availability of nutrients through vasculogenesis and by enhanced cellular entry of nutrients through upregulation of specific transporters. This review focuses on three groups of nutrient transporters relevant to cancer: glucose transporters, lactate transporters, and amino acid transporters. Tumor cells enhance glucose uptake via induction of GLUT1 and SGLT1, and coordinate the increased entry of glucose with increased glycolysis. Since enhanced glycolysis in cancer is associated with lactate production, tumor cells must find a way to eliminate lactic acid to prevent cellular acidification. This is achieved by the upregulation of MCT4, a H+-coupled lactate transporter. In addition, the Na+-coupled lactate transporter SMCT1 is silenced in cancer. SMCT1 also transports butyrate and pyruvate, which are inhibitors of histone deacetylases. The silencing of SMCT1 occurs in cancers of a variety of tissues. Re-expression of SMCT1 in cancer cell lines leads to growth arrest and apoptosis in the presence of butyrate or pyruvate, suggesting that the transporter may function as a tumor suppressor. Tumor cells meet their amino acid demands by inducing xCT/4F2hc, LAT1/4F2hc, ASCT2, and ATB0,+. xCT/4F2hc is related primarily to glutathione status, protection against oxidative stress, and cell cycle progression, whereas the other three transporters are related to amino acid nutrition. Pharmacologic blockade of LAT1/4F2hc, xCT/4F2hc, or ATB0,+ leads to inhibition of cancer cell growth. Since tumor cells selectively regulate these nutrient transporters to support their rapid growth, these transporters have potential as drug targets for cancer therapy.
KW - SLC16A1 (MCT1)/SLC16A3 (MCT4)
KW - SLC2A1 (GLUT1)/SLC5A1 (SGLT1)
KW - SLC5A8 (SMCT1)
KW - SLC6A14 (ATB)
KW - SLC7A11 (xCT)
KW - SLC7A5 (LAT1)
UR - http://www.scopus.com/inward/record.url?scp=57749111596&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=57749111596&partnerID=8YFLogxK
U2 - 10.1016/j.pharmthera.2008.09.005
DO - 10.1016/j.pharmthera.2008.09.005
M3 - Review article
C2 - 18992769
AN - SCOPUS:57749111596
SN - 0163-7258
VL - 121
SP - 29
EP - 40
JO - Pharmacology and Therapeutics
JF - Pharmacology and Therapeutics
IS - 1
ER -