2. Academic Validation
  3. The phospholipid flippase ATP9A enhances macropinocytosis to promote nutrient starvation tolerance in hepatocellular carcinoma

The phospholipid flippase ATP9A enhances macropinocytosis to promote nutrient starvation tolerance in hepatocellular carcinoma

  • J Pathol. 2023 Jan 30. doi: 10.1002/path.6059.
Xiaoqing Wang # 1,  Yue Li # 2,  Yunyun Xiao # 2,  Xinjian Huang # 2,  Xianqiu Wu 3 4,  Zhen Zhao 5 6,  Muwen Yang 2,  Lingzhi Kong 2,  Dongni Shi 2,  Xin Chen 7,  Ying Ouyang 2,  Xiangfu Chen 2,  Chuyong Lin 2,  Jun Li 8,  Libing Song 2,  Ye Lin 5,  Jian Guan 1 9
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
  • 2 Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, PR China.
  • 3 Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
  • 4 Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Jiangmen, PR China.
  • 5 Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, PR China.
  • 6 School of Medicine, South China University of Technology, Guangzhou, PR China.
  • 7 Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences; Guangzhou Institute of Oncology, Tumor Hospital, Guangzhou Medical University, Guangzhou, PR China.
  • 8 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 510080, Guangzhou, Guangdong, PR China.
  • 9 Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, PR China.
  • # Contributed equally.
PMID: 36715683 DOI: 10.1002/path.6059
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 characterized 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. This article is protected by copyright. All rights reserved.

Keywords

ATP6V1A; ATP9A; Hepatocellular carcinoma; macropinocytosis; nutrient starvation tolerance.

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