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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
GPR81 nuclear transportation is critical for cancer growth and progression in lung and other solid cancers
LiBang Yang, Thomas Kono, Adam Gilbertsen, Yingming Li, Bo Sun, Blake A Jacobson, Sabine Karam, Scott M Dehm, Craig A Henke, Robert A Kratzke
LiBang Yang, Adam Gilbertsen, Craig A Henke, Department of Medicine, University of Minnesota, Minnesota 55455, MN, United States
Thomas Kono, Minnesota Supercomputing Institute, University of Minnesota, Minnesota 55455, MN, United States
Yingming Li, Scott M Dehm, Masonic Cancer Center, Department of Medicine, University of Minnesota, Minnesota 55455, MN, United States
Bo Sun, Division of Gastro, Hepatology, Nutrition, Department of Medicine, University of Minnesota, Minnesota 55455, MN, United States
Blake A Jacobson, Robert A Kratzke, Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minnesota 55455, MN, United States
Sabine Karam, Division of Nephrology, Department of Medicine, University of Minnesota, Minnesota 55455, MN, United States
Author contributions: Yang L and Kratzke RA conceived, designed, and directed the studies; Henke CA, Karem S, Dehm SM provided cell lines and analyzed the data; Yang L, Gilbertsen A, Li Y, Sun B and Jacobson B established primary human cell lines, performed Q-PCR, western blot analysis, performed gain and loss of function experiments, mouse studies, and immunohistochemistry; Kono T processed and analyzed the ChIP seq data.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of the University of Minnesota.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the University of Minnesota.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The data that support the findings of this study are available on request from the corresponding author.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: LiBang Yang, MD, PhD, Senior Researcher, Department of Medicine, University of Minnesota, 420 Delaware Street, Minneapolis, MN 55455, United States.
yangx822@umn.edu
Received: March 18, 2025
Revised: May 19, 2025
Accepted: July 8, 2025
Published online: August 24, 2025
Processing time: 155 Days and 16.9 Hours
BACKGROUND
The Warburg effect is common in cancers. Lactate and its receptor GPR81 play an important role in cancer progression. It is widely accepted that membrane receptor nuclear translocation plays some novel role in cancer pathology. The mechanism by which the lactate/GPR81 axis regulates cancer malignancy remains unclear.
AIM
To elucidate the mechanism of GPR81 nuclear transportation promoted by exogenous lactate.
METHODS
Lung cancer cells were stimulated with exogenous lactate and GPR81 levels were measured by immunofluoresence and western blot analysis in membrane, cytoplasmic, and nuclear fractions. Lung cancer cells were transduced with a mutant GPR81 nuclear localization signal (NLS) construct, wild type GPR81 or empty vector and used to examine how GPR81 nuclear transportation affects lung cancer cells malignancy in vitro and in vivo. Immunoprecipitation Proteomics analysis and Chromatin immunoprecipitation (ChIP) sequencing were used to determine GPR81 interacting proteins and genes.
RESULTS
In response to hypoxia/Lactate stimulation, GPR81 translocates and accumulates in the nucleus of lung cancer cells. Functionally, GPR81 nuclear translocation promotes cancer cell proliferation and motility. Depletion of the GPR81 NLS depletes GPR81 nuclear levels and decreases cancer cell growth and invasion in vitro, as well as cancer cell malignancy in vivo. Proteomics analysis revealed a set of proteins including SFPQ, that interact with GPR81 in the cancer cell nucleus. Notably, the interaction of GPR81 with SFPQ promotes cancer cell growth and motility. ChIP sequencing analysis discovered that there is a set of genes targeted by GPR81.
CONCLUSION
The interaction of GPR81 with SFPQ promotes cancer cell malignancy. GPR81 nuclear translocation is critical in conferring cancer progression and may be a potential therapeutic target for limiting cancer progression.
Core Tip: Lactate promotes GPR81 expression and nuclear transportation. where GPR81 interacts with nuclear proteins and regulates cancer cell function. Then targeting GPR81 and its nuclear transportation provides an opportunity to develop novel treatments targeting cancers.
