Macropinocytosis confers resistance to therapies targeting cancer anabolism

被引:136
作者
Jayashankar, Vaishali [1 ]
Edinger, Aimee L. [1 ]
机构
[1] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92697 USA
基金
美国国家卫生研究院;
关键词
BREAST-CANCER; TUMOR NECROSIS; PHOSPHOINOSITIDE; 3-KINASE; PROGNOSTIC VALUE; KINASE AMPK; PROTEIN; AUTOPHAGY; INHIBITION; EXPRESSION; MUTATIONS;
D O I
10.1038/s41467-020-14928-3
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Macropinocytic cancer cells scavenge amino acids from extracellular proteins. Here, we show that consuming necrotic cell debris via macropinocytosis (necrocytosis) offers additional anabolic benefits. A click chemistry-based flux assay reveals that necrocytosis provides not only amino acids, but sugars, fatty acids and nucleotides for biosynthesis, conferring resistance to therapies targeting anabolic pathways. Indeed, necrotic cell debris allow macropinocytic breast and prostate cancer cells to proliferate, despite fatty acid synthase inhibition. Standard therapies such as gemcitabine, 5-fluorouracil (5-FU), doxorubicin and gamma-irradiation directly or indirectly target nucleotide biosynthesis, creating stress that is relieved by scavenged nucleotides. Strikingly, necrotic debris also render macropinocytic, but not non-macropinocytic, pancreas and breast cancer cells resistant to these treatments. Selective, genetic inhibition of macropinocytosis confirms that necrocytosis both supports tumor growth and limits the effectiveness of 5-FU in vivo. Therefore, this study establishes necrocytosis as a mechanism for drug resistance. Macropinocytosis allows cancer cells to cope with nutrient stress. Here, the authors use a selective, genetic approach to inhibit macropinocytosis and show that consuming necrotic cell debris via macropinocytosis-necrocytosis-affords resistance to many therapies that target biosynthesis.
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页数:15
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