SCFFBXW5-mediated degradation of AQP3 suppresses autophagic cell death through the PDPK1-AKT-MTOR axis in hepatocellular carcinoma cells

Autophagy. 2024 Sep;20(9):1984-1999. doi: 10.1080/15548627.2024.2353497. Epub 2024 May 18.

Abstract

AQP3 (aquaporin 3 (Gill blood group)), a member of the AQP family, is an aquaglyceroporin which transports water, glycerol and small solutes across the plasma membrane. Beyond its role in fluid transport, AQP3 plays a significant role in regulating various aspects of tumor cell behavior, including cell proliferation, migration, and invasion. Nevertheless, the underlying regulatory mechanism of AQP3 in tumors remains unclear. Here, for the first time, we report that AQP3 is a direct target for ubiquitination by the SCFFBXW5 complex. In addition, we revealed that downregulation of FBXW5 significantly induced AQP3 expression to prompt macroautophagic/autophagic cell death in hepatocellular carcinoma (HCC) cells. Mechanistically, AQP3 accumulation induced by FBXW5 knockdown led to the degradation of PDPK1/PDK1 in a lysosomal-dependent manner, thus inactivating the AKT-MTOR pathway and inducing autophagic death in HCC. Taken together, our findings revealed a previously undiscovered regulatory mechanism through which FBXW5 degraded AQP3 to suppress autophagic cell death via the PDPK1-AKT-MTOR axis in HCC cells.Abbreviation: BafA1: bafilomycin A1; CQ: chloroquine; CRL: CUL-Ring E3 ubiquitin ligases; FBXW5: F-box and WD repeat domain containing 5; HCC: hepatocellular carcinoma; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; 3-MA: 3-methyladenine; PDPK1/PDK1: 3-phosphoinositide dependent protein kinase 1; RBX1/ROC1: ring-box 1; SKP1: S-phase kinase associated protein 1; SCF: SKP1-CUL1-F-box protein.

Keywords: AQP3; FBXW5; PDPK1-AKT-MTOR pathway; autophagic cell death; hepatocellular carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases* / metabolism
  • Animals
  • Aquaporin 3* / genetics
  • Aquaporin 3* / metabolism
  • Autophagy* / physiology
  • Carcinoma, Hepatocellular* / metabolism
  • Carcinoma, Hepatocellular* / pathology
  • Cell Line, Tumor
  • F-Box Proteins* / metabolism
  • Humans
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / pathology
  • Lysosomes / metabolism
  • Proteolysis
  • Proto-Oncogene Proteins c-akt* / metabolism
  • Signal Transduction*
  • TOR Serine-Threonine Kinases* / metabolism
  • Ubiquitination

Substances

  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • 3-Phosphoinositide-Dependent Protein Kinases
  • Aquaporin 3
  • PDPK1 protein, human
  • F-Box Proteins
  • MTOR protein, human
  • AQP3 protein, human

Grants and funding

This work was funded by the Shanghai Frontiers Science Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation [2021KJ03-12], the National Natural Science Foundation of China [82002973, 82372984, 82272987, 82172933], the Chinese Minister of Science and Technology grant [2016YFA0501800], Science and Technology Commission of Shanghai Municipality [21ZR1482200], Shanghai Rising-Star Program [23QA1403000].