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- Title
The phospholipid flippase ATP9A enhances macropinocytosis to promote nutrient starvation tolerance in hepatocellular carcinoma.
- Authors
Wang, Xiaoqing; Li, Yue; Xiao, Yunyun; Huang, Xinjian; Wu, Xianqiu; Zhao, Zhen; Yang, Muwen; Kong, Lingzhi; Shi, Dongni; Chen, Xin; Ouyang, Ying; Chen, Xiangfu; Lin, Chuyong; Li, Jun; Song, Libing; Lin, Ye; Guan, Jian
- Abstract
Macropinocytosis is an effective strategy to mitigate nutrient starvation. It can fuel cancer cell growth in nutrient‐limited conditions. However, whether and how macropinocytosis contributes to the rapid proliferation of hepatocellular carcinoma cells, which frequently experience an inadequate nutrient supply, remains unclear. Here, we demonstrated that nutrient starvation strongly induced macropinocytosis in some hepatocellular carcinoma cells. It allowed the cells to acquire extracellular nutrients and supported their energy supply to maintain rapid proliferation. Furthermore, we found that the phospholipid flippase ATP9A was critical for regulating macropinocytosis in hepatocellular carcinoma cells and that high ATP9A levels predicted a poor outcome for patients with hepatocellular carcinoma. ATP9A interacted with ATP6V1A and facilitated its transport to the plasma membrane, which promoted plasma membrane cholesterol accumulation and drove RAC1‐dependent macropinocytosis. Macropinocytosis inhibitors significantly suppressed the energy supply and proliferation of hepatocellular carcinoma cells characterised by high ATP9A expression under nutrient‐limited conditions. These results have revealed a novel mechanism that overcomes nutrient starvation in hepatocellular carcinoma cells and have identified the key regulator of macropinocytosis in hepatocellular carcinoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
- Subjects
JOHN Wiley &; Sons Inc.; PINOCYTOSIS; HEPATOCELLULAR carcinoma; CANCER cell growth; STARVATION; CELL membranes
- Publication
Journal of Pathology, 2023, Vol 260, Issue 1, p17
- ISSN
0022-3417
- Publication type
Article
- DOI
10.1002/path.6059