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ZDHHC2-Mediated AGK Palmitoylation Activates AKT–mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma

Tyrosine kinase inhibitors (TKI) that can suppress the VEGF signaling pathway and angiogenesis have been developed to impede the progression of malignant tumors and have been approved as first-line targeted agents for clear cell renal cell carcinoma (ccRCC). Dysregulation of lipid metabolism is a ma...

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Autores principales: Sun, Yan, Zhu, Liang, Liu, Pian, Zhang, Huan, Guo, Feng, Jin, Xin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10267682/
https://www.ncbi.nlm.nih.gov/pubmed/37078777
http://dx.doi.org/10.1158/0008-5472.CAN-22-3105
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author Sun, Yan
Zhu, Liang
Liu, Pian
Zhang, Huan
Guo, Feng
Jin, Xin
author_facet Sun, Yan
Zhu, Liang
Liu, Pian
Zhang, Huan
Guo, Feng
Jin, Xin
author_sort Sun, Yan
collection PubMed
description Tyrosine kinase inhibitors (TKI) that can suppress the VEGF signaling pathway and angiogenesis have been developed to impede the progression of malignant tumors and have been approved as first-line targeted agents for clear cell renal cell carcinoma (ccRCC). Dysregulation of lipid metabolism is a major driver of TKI resistance in renal cancer. In this study, we showed that the palmitoyl acyltransferase ZDHHC2 is abnormally upregulated in tissues and cell lines resistant to TKIs, such as sunitinib. Upregulation of ZDHHC2 contributed to sunitinib resistance in cells and mice, and ZDHHC2 regulated angiogenesis and cell proliferation in ccRCC. Mechanistically, ZDHHC2 mediated AGK S-palmitoylation to promote translocation of AGK into the plasma membrane and activation of the PI3K–AKT–mTOR signaling pathway in ccRCC, which modulated sunitinib sensitivity. In conclusion, these results identify a ZDHHC2–AGK signaling axis and suggest that ZDHHC2 is a targetable candidate for improving the antitumor efficacy of sunitinib in ccRCC. SIGNIFICANCE: ZDHHC2 confers sunitinib resistance to clear cell renal cell carcinoma by catalyzing AGK palmitoylation to activate the AKT–mTOR pathway.
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spelling pubmed-102676822023-06-15 ZDHHC2-Mediated AGK Palmitoylation Activates AKT–mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma Sun, Yan Zhu, Liang Liu, Pian Zhang, Huan Guo, Feng Jin, Xin Cancer Res Cancer Metabolism and Molecular Mechanisms Tyrosine kinase inhibitors (TKI) that can suppress the VEGF signaling pathway and angiogenesis have been developed to impede the progression of malignant tumors and have been approved as first-line targeted agents for clear cell renal cell carcinoma (ccRCC). Dysregulation of lipid metabolism is a major driver of TKI resistance in renal cancer. In this study, we showed that the palmitoyl acyltransferase ZDHHC2 is abnormally upregulated in tissues and cell lines resistant to TKIs, such as sunitinib. Upregulation of ZDHHC2 contributed to sunitinib resistance in cells and mice, and ZDHHC2 regulated angiogenesis and cell proliferation in ccRCC. Mechanistically, ZDHHC2 mediated AGK S-palmitoylation to promote translocation of AGK into the plasma membrane and activation of the PI3K–AKT–mTOR signaling pathway in ccRCC, which modulated sunitinib sensitivity. In conclusion, these results identify a ZDHHC2–AGK signaling axis and suggest that ZDHHC2 is a targetable candidate for improving the antitumor efficacy of sunitinib in ccRCC. SIGNIFICANCE: ZDHHC2 confers sunitinib resistance to clear cell renal cell carcinoma by catalyzing AGK palmitoylation to activate the AKT–mTOR pathway. American Association for Cancer Research 2023-06-15 2023-04-20 /pmc/articles/PMC10267682/ /pubmed/37078777 http://dx.doi.org/10.1158/0008-5472.CAN-22-3105 Text en ©2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Cancer Metabolism and Molecular Mechanisms
Sun, Yan
Zhu, Liang
Liu, Pian
Zhang, Huan
Guo, Feng
Jin, Xin
ZDHHC2-Mediated AGK Palmitoylation Activates AKT–mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma
title ZDHHC2-Mediated AGK Palmitoylation Activates AKT–mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma
title_full ZDHHC2-Mediated AGK Palmitoylation Activates AKT–mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma
title_fullStr ZDHHC2-Mediated AGK Palmitoylation Activates AKT–mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma
title_full_unstemmed ZDHHC2-Mediated AGK Palmitoylation Activates AKT–mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma
title_short ZDHHC2-Mediated AGK Palmitoylation Activates AKT–mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma
title_sort zdhhc2-mediated agk palmitoylation activates akt–mtor signaling to reduce sunitinib sensitivity in renal cell carcinoma
topic Cancer Metabolism and Molecular Mechanisms
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10267682/
https://www.ncbi.nlm.nih.gov/pubmed/37078777
http://dx.doi.org/10.1158/0008-5472.CAN-22-3105
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