SCF^FBXW5-mediated degradation of AQP3 suppresses autophagic cell death through the PDPK1-AKT-MTOR axis in hepatocellular carcinoma cells

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 SCF^FBXW5 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
• autophagic cell death
• FBXW5
• hepatocellular carcinoma
• PDPK1-AKT-MTOR pathway

Acknowledgements

We wish to extend our heartfelt thanks to Dr. Xiao Biying of the Longhua Hospital for her generous contribution of the pc3.1-FLAG-AQP3 plasmid.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data analyzed during this study are included in this published article and the supplemental data files. Additional supporting data are available from the corresponding authors upon reasonable request.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15548627.2024.2353497.

Additional information

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].