2. Academic Validation
  3. Palmitoylation alters LDHA activity and pancreatic cancer response to chemotherapy

Palmitoylation alters LDHA activity and pancreatic cancer response to chemotherapy

  • Cancer Lett. 2024 Feb 6:587:216696. doi: 10.1016/j.canlet.2024.216696.
Luojun Chen 1,  Xiaoke Xing 1,  Yue Zhu 2,  Yali Chen 3,  Huadong Pei 4,  Qibin Song 5,  Juanjuan Li 6,  Pingfeng Zhang 7
Affiliations

Affiliations

  • 1 Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430062, Hubei, China.
  • 2 Department of Radiotherapy, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
  • 3 State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China.
  • 4 Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, 20057, DC, USA. Electronic address: huadong.pei@georgetown.edu.
  • 5 Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430062, Hubei, China. Electronic address: qibinsong@whu.edu.cn.
  • 6 Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, 430062, Hubei, China. Electronic address: juanjuan.li@whu.edu.cn.
  • 7 Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430062, Hubei, China. Electronic address: pingfeng.zhang@whu.edu.cn.
PMID: 38331089 DOI: 10.1016/j.canlet.2024.216696
Abstract

Lactate Dehydrogenase A (LDHA) serves as a key regulator of the Warburg Effect by catalyzing the conversion of pyruvate to lactate in the final step of glycolysis. Both the expression level and Enzyme activity of LDHA are upregulated in cancers, however, the underlying mechanism remains incompletely understood. Here, we show that LDHA is post-translationally palmitoylated by ZDHHC9 at cysteine 163, which promotes its Enzyme activity, lactate production, and reduces Reactive Oxygen Species (ROS) generation. Replacement of endogenous LDHA with a palmitoylation-deficient mutant leads to reduced pancreatic Cancer cell proliferation, increased T-cell infiltration, and limited tumor growth; it also affects pancreatic Cancer cell response to chemotherapy. Moreover, LDHA palmitoylation is upregulated in gemcitabine resistant pancreatic Cancer cells. Clinically, ZDHHC9 is upregulated in pancreatic Cancer and correlated with poor prognoses for patients. Overall, our findings identify ZDHHC9-mediated palmitoylation as a positive regulator of LDHA, with potentially significant implications for Cancer etiology and targeted therapy for pancreatic Cancer.

Keywords

Gemcitabine; LDHA; Palmitoylation; Pancreatic cancer; ZDHHC9.

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