PTEN deficiency and AMPK activation promote nutrient scavenging and anabolism in prostate cancer cells

Seong M. Kim, Tricia T. Nguyen, Archna Ravi, Peter Kubiniok, Brendan T. Finicle, Vaishali Jayashankar, Leonel Malacrida, Jue Hou, Jane Robertson, Dong Gao, Jonathan Chernoff, Michelle A. Digman, Eric O. Potma, Bruce J. Tromberg, Pierre Thibault, Aimee L. Edinger

Research output: Contribution to journalArticlepeer-review

154 Scopus citations

Abstract

We report that PTEN-deficient prostate cancer cells use macropinocytosis to survive and proliferate under nutrient stress. PTEN loss increased macropinocytosis only in the context of AMPK activation, revealing a general requirement for AMPK in macropinocytosis and a novel mechanism by which AMPK promotes survival under stress. In prostate cancer cells, albumin uptake did not require macropinocytosis, but necrotic cell debris proved a specific macropinocytic cargo. Isotopic labeling confirmed that macropinocytosed necrotic cell proteins fueled new protein synthesis in prostate cancer cells. Supplementation with necrotic debris, but not albumin, also maintained lipid stores, suggesting that macropinocytosis can supply nutrients other than amino acids. Non-transformed prostatic epithelial cells were not macropinocytic, but patient-derived prostate cancer organoids and xenografts and autochthonous prostate tumors all exhibited constitutive macropinocytosis, and blocking macropinocytosis limited prostate tumor growth. Macropinocytosis of extracellular material by prostate cancer cells is a previously unappreciated tumor–microenvironment interaction that could be targeted therapeutically. SIGNIFICANCE: As PTEN-deficient prostate cancer cells proliferate in low-nutrient environments by scavenging necrotic debris and extracellular protein via macropinocytosis, blocking macropinocytosis by inhibiting AMPK, RAC1, or PI3K may have therapeutic value, particularly in necrotic tumors and in combination with therapies that cause nutrient stress.

Original languageEnglish
Pages (from-to)866-883
Number of pages18
JournalCancer Discovery
Volume8
Issue number7
DOIs
StatePublished - Jul 2018

Keywords

  • AMP-Activated Protein Kinases/metabolism
  • Animals
  • Gene Deletion
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nutrients/metabolism
  • PTEN Phosphohydrolase/genetics
  • Pinocytosis
  • Prostatic Neoplasms/metabolism
  • Stress, Physiological

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