Metabolic and Nonmetabolic Functions of PSAT1 Coordinate Signaling Cascades to Confer EGFR Inhibitor Resistance and Drive Progression in Lung Adenocarcinoma.

Abstract

Emerging evidence demonstrates that the dysregulated metabolic enzymes can accelerate tumorigenesis and progression via both metabolic and nonmetabolic functions. Further elucidation of the role of metabolic enzymes in EGFR inhibitor resistance and metastasis, two of the leading causes of death in lung adenocarcinoma, could help improve patient outcomes. Here, we found that aberrant upregulation of phosphoserine aminotransferase 1 (PSAT1) confers erlotinib resistance and tumor metastasis in lung adenocarcinoma. Depletion of PSAT1 restored sensitivity to erlotinib and synergistically augmented the tumoricidal effect. Mechanistically, inhibition of PSAT1 activated the ROS-dependent JNK/c-Jun pathway to induce cell apoptosis. In addition, PSAT1 interacted with IQGAP1, subsequently activating STAT3-mediated cell migration independent of its metabolic activity. Clinical analyses showed that PSAT1 expression positively correlated with the progression of human lung adenocarcinoma. Collectively, these findings reveal the multifunctionality of PSAT1 in promoting tumor malignancy through its metabolic and nonmetabolic activities.

SIGNIFICANCE:

Metabolic and nonmetabolic functions of PSAT1 confer EGFR inhibitor resistance and promote metastasis in lung adenocarcinoma, suggesting therapeutic targeting of PSAT1 may attenuate the malignant features of lung cancer.

• Authors: Ming-Yu Luo, Ye Zhou, Wei-Ming Gu, Cheng Wang, Ning-Xiang Shen, Jiang-Kai Dong, Hui-Min Lei, Ya-Bin Tang, Qian Liang, Jing-Hua Zou, Lu Xu, Pengfei Ma, Guanglei Zhuang, Ling Bi, Ling Xu, Liang Zhu, Hong-Zhuan Chen, Ying Shen
• Journal: Cancer research (Cancer Res) Vol. 82 Issue 19 Pg. 3516-3531 (Oct 04 2022) ISSN: 1538-7445 [Electronic] United States
• PMID: 36193649 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• Protein Kinase Inhibitors
• Reactive Oxygen Species
• Erlotinib Hydrochloride
• Transaminases
• EGFR protein, human
• ErbB Receptors

Topics

• Adenocarcinoma of Lung (pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• ErbB Receptors
• Erlotinib Hydrochloride (pharmacology, therapeutic use)
• Humans
• Lung Neoplasms (pathology)
• Protein Kinase Inhibitors (pharmacology)
• Reactive Oxygen Species (metabolism)
• Transaminases (metabolism)