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

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.

NHE7 upregulation potentiates the uptake of small extracellular vesicles by enhancing maturation of macropinosomes in hepatocellular carcinoma

“…Under hypoxic conditions, macropinocytosis is induced by the elevation of EH domain‐containing protein 2 expression to engulf extracellular nutrients for survival [ 36 ]. Macropinocytosis mediated by ATPase phospholipid transporting 9A (ATP9A) promotes nutrient starvation tolerance in HCC [ 37 ]. It has been shown to internalize and sort the C‐X‐C chemokine receptor type 4 (CXCR4) chemokine receptor to recycling endosomes [ 38 ].…”

Type IV P-Type ATPases: Recent Updates in Cancer Development, Progression, and Treatment

“…Macropinocytosis, an important process that fuels cancer cell proliferation by scavenging extracellular proteins or necrotic cell debris, is critical for sustaining HCC proliferation and growth under nutrient limitation. The interaction of ATP9A with ATP6V1A facilitated ATP6V1A membrane trafficking, thereby activating plasma membrane cholesterol-dependent RAC1 signaling and initiating macropinocytosis to increase the energy supply and support HCC cell survival and proliferation [73]. Another study detected that miR-103a was one of the most highly expressed microRNAs in HCC tissues and that a high expression of miR-103a was associated with poor patient prognosis.…”

“…However, a next-generation transcriptome sequencing study of three human hepatocellular carcinoma (HCC) tumor/tumor-adjacent pairs, followed by validation of differential gene expression findings in a large data set consisting of 434 liver normal/tumor sample pairs, revealed non-synonymous mutations in ATP8B1 as liver cancer driver mutations [48]. On the other hand, for patients with HCC, high ATP9A levels predicted a poor outcome [73]. In hepatocellular carcinoma cells, ATP9A was critical for regulating macropinocytosis via interaction with ATP6V1A resulting in plasma membrane cholesterol accumulation.…”