Cover article Serine Aminotransferase Phosphate 1 (PSAT1) promotes a new mechanism for resistance and metastasis of EGFR-TKIs in lung adenocarcinoma

On October 4, Shen Ying's research group in the Department of Pharmacology and Chemical Biology of Shanghai Jiao Tong University School of Medicine published a cover article "Metabolic and non-metabolic functions of PSAT1 coordinate signaling cascades to confer EGFR-inhibitor resistance and" in Cancer Research, a classic journal in the field of oncology research drive progression in lung adenocarcinoma", revealing that PSAT1 combines metabolic enzyme activity and non-metabolically regulated protein interaction, synergistically regulates ROS/JNK/c-Jun and IQGAP1-STAT3 signaling axes, and jointly promotes innovative mechanisms for
drug resistance and metastasis of lung adenocarcinoma.

As shown on the cover: Serine Aminotransferase Phosphate 1 (PSAT1) is like a high-speed mechanical turntable, loaded with a flexible and delicate robotic arm (metabolic enzyme activity) on top to regulate intracellular redox balance (red and blue bubbles), loaded with free elliptical suction cups (protein interaction function), recruited and activated IQGAP1-STAT3 signal axis (purple-powder protein cartoon), and jointly promoted lung adenocarcinoma resistance and metastasis
to Erlotinib 。 Recently, a number of research papers and reviews have been published in the journal Cancer Research to explore the relationship between metabolic reprogramming and its key enzymes in the malignant progression of tumors and clinical prognosis, and Shen Ying's team article was honored to be selected as the cover of the current issue, which fully reflects the important findings and potential leading role of the paper, and also vividly demonstrates the scientific concepts and innovations contained in
the research results.

Cancer Research Cover Article (2022 Oct 1; 82(19):3516–31）

PSAT1 combines metabolic enzyme activity with non-metabolically regulated protein interaction

Shen Ying, a researcher at Shanghai Jiao Tong University School of Medicine, is the corresponding author of
the paper.
Luo Mingyu, a 2021 doctoral candidate at Shanghai Jiao Tong University School of Medicine, and Zhou Ye and Gu Weiming, graduated master's students, were co-first authors of
the paper.
The work has been guided and supported by Professor Chen Hongzhuan of the Institute of Interdisciplinary Sciences of Shanghai University of Traditional Chinese Medicine, Professor Zhu Liang of Shanghai Jiao Tong University School of Medicine, Zhuang Guanglei of Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Professor Xu Ling of Yueyang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, as well as the Shanghai Collaborative Innovation Center for Biomedical Clinical Research and Transformation, the Key Laboratory of Cell Differentiation and Apoptosis of the Ministry of Education, the Frontier Science Center of Cell Stationary Regulation of Diseases, and the Collaborative Innovation Center for Biomedical Clinical Research and Transformation jointly established by the Ministry of Education.
The public technology platform of Shanghai Jiao Tong University School of Basic Medicine provides strong support; The project has been funded
by the National Natural Science Foundation of China and the Shanghai Municipal Science and Technology Commission.

Expert reviews

Professor Fu Hai'an Emory University, USA

Every time we celebrate the success of a new generation of anti-cancer drugs, tumors have built barriers to drug resistance, leading to reduced efficacy and even the failure
of treatment.
Therefore, revealing the rewired oncogenic programs and anti-drug resistance molecular mechanisms within tumors is of great significance
to our development of new drugs and clinical applications.
In recent years, more and more research has elucidated that tumor metabolic enzymes have multiple functions of both metabolic enzyme activity and non-metabolic regulation, which play an important role in the malignant progression of tumors and have become the forefront of new target research of anti-tumor drugs
.
However, the relevant research on the multiple functions of tumor metabolic enzymes has not been thoroughly studied
.
Erlotinib and other epidermal growth factor receptor tyrosine kinase (EGFR) inhibitor molecular targeted drugs have remarkable efficacy in the treatment of lung adenocarcinoma, but they are extremely resistant and cause tumor recurrence and metastasis in patients, and in-depth study of tumor drug resistance and metastasis of tumor metabolic enzymes can help improve tumor treatment strategies
.

PSAT1 is one of the key enzymes in the serine synthesis pathway, which catalyzes the conversion of hydroxypyruvate 3-phosphate (3-PPyr) into serine phosphate (p-serine), which can further produce serine and glycine, and participate in downstream monocarbon metabolism and nucleic acid metabolism; PSAT1 simultaneously catalyzes the production of glutamic acid in cells α-ketoglutaric acid (α-KG) into the tricarboxylic acid cycle, participates in the regulation of complex metabolic networks, provides tumor cells with the material basis and energy required for proliferation, and maintains intracellular redox balance
.

On October 4, 2022, Shen Ying's research group of Shanghai Jiao Tong University School of Medicine published a long article entitled "Metabolic and non-metabolic functions of PSAT1 coordinate signaling cascades to confer EGFR-inhibitor resistance" in Cancer Research And drive progression in lung adenocarcinoma" cover article, reported that PSAT1, a key enzyme in the serine synthesis pathway, combines classical metabolic enzyme activity and non-metabolically regulated protein interaction function, synergistically regulates ROS/JNK/c-Jun and IQGAP1-STAT3 signaling axes, and promotes lung adenocarcinoma resistance and metastasis
to EGFR inhibitors.

This study found that during the short-term adaptive resistance and long-term acquired resistance of lung adenocarcinoma cells, serine synthesized from de novo and its key enzymes in the synthesis pathway PHGDH, PSAT1 and PSPH proteins increased
significantly.
Knocking down PSAT1 can preferentially inhibit the proliferation and movement of drug-resistant cells, restore the sensitivity of drug-resistant cells to Erlotinib, and enhance the killing effect
of Erlotinib on lung adenocarcinoma.
Conversely, overexpression of PSAT1 promotes Erlotinib resistance and tumor metastasis
in lung adenocarcinoma.
Mechanism studies have shown that PSAT1 not only regulates the redox homeostasis in lung adenocarcinoma cells through serine synthesis pathway, but also does not rely on its classical metabolic enzyme activity, interacts with IQGAP1 protein, and then recruits and activates the downstream STAT3 signaling pathway, thereby promoting drug resistance and metastasis
of lung adenocarcinoma EGFR-TKIs.
The results of clinical sample database analysis confirmed that PSAT1 levels were significantly and positively correlated with malignant progression and metastasis in patients with lung adenocarcinoma, and that the PSAT1-IQGAP1-STAT3 signal axis was closely related
to the poor prognosis of patients.

This research result reveals the new mechanism of PSAT1 promoting drug resistance and metastasis of lung adenocarcinoma EGFR-TKIs, provides an experimental theoretical basis for in-depth study of the relationship between PSAT1 and the malignant progression of lung adenocarcinoma, and provides new ideas
for the targeted design of antitumor drugs targeting PSAT1.
It is worth noting that previous studies have reported that tumor-specific protein-protein interactions (OncoPPIs) are widespread, providing rich resources and huge opportunities
for exploring potential new anti-cancer drug targets.
Further research into the newly discovered PSAT1 and PSAT1-IQGAP1 oncoPPI for lung adenocarcinoma is expected to accelerate the development
of a new generation of anticancer drugs.