PTEN Deficiency and AMPK Activation Promote Nutrient Scavenging and Anabolism in Prostate Cancer Cells.
PTEN Deficiency and AMPK Activation Promote Nutrient Scavenging and Anabolism in Prostate Cancer Cells.
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DOI：
10.1158/2159-8290.cd-17-1215
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发表时间：
2018-07
期刊：
影响因子：
28.2
通讯作者：
Edinger AL
中科院分区：
文献类型：
--
作者：
Kim SM;Nguyen TT;Ravi A;Kubiniok P;Finicle BT;Jayashankar V;Malacrida L;Hou J;Robertson J;Gao D;Chernoff J;Digman MA;Potma EO;Tromberg BJ;Thibault P;Edinger AL
我们报告说，PTEN 缺陷的前列腺癌细胞利用巨胞饮作用在营养应激下生存和增殖。 PTEN 缺失仅在 AMPK 激活的情况下增加巨胞饮作用，揭示了巨胞饮作用中对 AMPK 的一般要求以及 AMPK 促进应激下生存的新机制。在前列腺癌细胞中，白蛋白的摄取不需要巨胞饮作用，但坏死的细胞碎片被证明是一种特定的巨胞饮作用。同位素标记证实，巨胞饮坏死细胞蛋白促进了前列腺癌细胞中新蛋白的合成。补充坏死碎片而不是白蛋白也能维持脂质储存，这表明巨胞饮作用可以提供氨基酸以外的营养物质。未转化的前列腺上皮细胞不具有巨胞饮作用，但患者来源的前列腺癌类器官和异种移植物以及本地前列腺肿瘤均表现出组成型巨胞饮作用，并且阻断巨胞饮作用限制了前列腺肿瘤的生长。前列腺癌细胞对细胞外物质的巨胞饮作用是一种以前未被认识到的肿瘤-微环境相互作用，可以作为治疗靶点。
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.