PTEN Deficiency and AMPK Activation Promote Nutrient Scavenging and Anabolism in Prostate Cancer Cells
| Autor: | Seong M. Kim, Pierre Thibault, Brendan T. Finicle, Dong Gao, Michelle A. Digman, Leonel Malacrida, Jue Hou, Aimee L. Edinger, Vaishali Jayashankar, Jane Robertson, Jonathan Chernoff, Bruce J. Tromberg, Archna Ravi, Peter Kubiniok, Eric O. Potma, Tricia T. Nguyen |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Male
Urologic Diseases 0301 basic medicine Aging Physiological Oncology and Carcinogenesis Context (language use) RAC1 AMP-Activated Protein Kinases Inbred C57BL Stress Article Mice 03 medical and health sciences Prostate cancer Stress Physiological Prostate medicine Animals Humans 2.1 Biological and endogenous factors PTEN Aetiology PI3K/AKT/mTOR pathway Cancer Nutrition biology Chemistry Prostate Cancer PTEN Phosphohydrolase Prostatic Neoplasms AMPK Nutrients medicine.disease Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Oncology biology.protein Cancer research Pinocytosis Gene Deletion |
| Zdroj: | Cancer discovery, vol 8, iss 7 |
| ISSN: | 2159-8290 2159-8274 |
| Popis: | 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. Nontransformed 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. Cancer Discov; 8(7); 866-83. ©2018 AACR.See related commentary by Commisso and Debnath, p. 800This article is highlighted in the In This Issue feature, p. 781. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|