PTEN-deficient prostate cancer cells survive and proliferate in low-nutrient environments by using macropinocytosis to scavenge extracellular proteins and necrotic debris, according to a new study.
Anabolism and proliferation of cancer cells is fuelled by the upregulation of nutrient acquisition pathways, but as tumours grow, nutrients become limited and tumour necrosis can occur. “Activating mutations in Ras confer resistance to nutrient stress by stimulating scavenging of extracellular protein via macropinocytosis,” says Aimee Edinger, an author on the new paper. “PI3K activity is necessary for macropinocytosis downstream from Ras, and so we hypothesized that prostate cancer cells deficient in PTEN (which opposes the PI3K pathway) might also exhibit macropinocytosis and resistance to nutrient stress.”
The researchers showed that neither PTEN-knockout nor PTEN-wild-type murine embryonic fibroblasts (MEFs) took up the macropinocytic cargos dextran and bovine serum albumin (BSA) in complete medium. However, in low-nutrient medium, dextran and BSA uptake was greatly increased in PTEN-knockout MEFs. The increased uptake was consistent with internalization via macropinocytosis.
“increased uptake was consistent with internalization via macropinocytosis”
The study also showed that PTEN loss alone is not enough to drive macropinocytosis: AMPK activation is also needed for PTEN-deficient MEFs to form macropinosomes and proliferate under nutrient-limiting conditions. “Knockout MEFs that were deficient in either ATG5 or PAK1 also enabled us to demonstrate that macropinocytosis trumps autophagy as a nutrient stress response,” notes Edinger. “Cells can survive using autophagy but they can both survive and proliferate using macropinocytosis.”
The authors showed that necrotic cell debris is taken up by prostate cancer cells by macropinocytosis. They also used patient samples and autochthonous tumour models to confirm that macropinocytosis occurred in primary prostate tumour samples and in a physiological context.
“Showing that AMPK activation can drive growth in low-nutrient medium by stimulating macropinocytosis adds to the growing body of literature suggesting that inhibiting — rather than activating — AMPK in established prostate tumours could be a superior therapeutic strategy,” says Edinger.
Kim, S. M. et al. PTEN deficiency and AMPK activation promote nutrient scavenging and anabolism in prostate cancer cells. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-17-1215 (2018)
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Kelsey, R. Macropinocytosis for proliferation. Nat Rev Urol 15, 336–337 (2018). https://doi.org/10.1038/s41585-018-0012-2
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