Nutrient transporters in cancer: Relevance to Warburg hypothesis and beyond

Research output: Contribution to journalReview article

415 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)29-40
Number of pages12
JournalPharmacology and Therapeutics
Volume121
Issue number1
DOIs
StatePublished - Jan 1 2009

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Food
Neoplasms
Monocarboxylic Acid Transporters
Butyrates
Glycolysis
Lactic Acid
Up-Regulation
Growth
Amino Acid Transport Systems
Amino Acids
Glucose
Histone Deacetylases
Facilitative Glucose Transport Proteins
Pyruvic Acid
Glutathione
Cell Cycle
Oxidative Stress
Apoptosis
Cell Line
Pharmaceutical Preparations

Keywords

  • SLC16A1 (MCT1)/SLC16A3 (MCT4)
  • SLC2A1 (GLUT1)/SLC5A1 (SGLT1)
  • SLC5A8 (SMCT1)
  • SLC6A14 (ATB)
  • SLC7A11 (xCT)
  • SLC7A5 (LAT1)

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Nutrient transporters in cancer : Relevance to Warburg hypothesis and beyond. / Ganapathy, Vadivel; Thangaraju, Muthusamy; Prasad, Puttur D.

In: Pharmacology and Therapeutics, Vol. 121, No. 1, 01.01.2009, p. 29-40.

Research output: Contribution to journalReview article

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