Gastric cancer (GC) is among the most lethal human malignancies, yet it remains hampered by challenges in fronter of molecular-guided targeted therapy to direct clinical treatment strategies. The protein tyrosine phosphatase Src homology 2 domain-containing phosphatase 2 (SHP2) is involved in the malignant progression of GC. However, the detailed mechanisms of the posttranslational modifications of SHP2 remain poorly understood. Herein, we demonstrated that an allosteric SHP2 inhibitor, SHP099, was able to block tumor proliferation and migration of GC by dephosphorylating the pyruvate kinase M2 type (PKM2) protein. Mechanistically, we found that PKM2 is a bona fide target of SHP2. The dephosphorylation and activation of PKM2 by SHP2 are necessary to exacerbate tumor progression and GC glycolysis. Moreover, we demonstrated a strong correlation between the phosphorylation level of PKM2 and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) in GC cells. Notably, the low phosphorylation expression of AMPK was negatively correlated with activated SHP2. Besides, we proved that cisplatin could activate SHP2 and SHP099 increased sensitivity to cisplatin in GC. Taken together, our results provide evidence that the SHP2/PKM2/AMPK axis exerts a key role in GC progression and glycolysis and could be a viable therapeutic approach for the therapy of GC.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10993348PMC
http://dx.doi.org/10.1002/mco2.527DOI Listing

Publication Analysis

Top Keywords

progression glycolysis
12
tyrosine phosphatase
8
shp2
8
phosphatase shp2
8
tumor progression
8
gastric cancer
8
pkm2
5
shp2 aggravates
4
aggravates tumor
4
progression
4

Similar Publications

The word "cancer" evokes myriad emotions, ranging from fear and despair to hope and determination. Cancer is aptly defined as a complex and multifaceted group of diseases that has unapologetically led to the loss of countless lives and affected innumerable families across the globe. The battle with cancer is not only a physical battle, but also an emotional, as well as a psychological skirmish for patients and for their loved ones.

View Article and Find Full Text PDF

Lactate, long viewed as a byproduct of glycolysis and metabolic waste. Initially identified within the context of yogurt fermentation, lactate's role extends beyond culinary applications to its significance in biochemical processes. Contemporary research reveals that lactate functions not merely as the terminal product of glycolysis but also as a nexus for initiating physiological and pathological responses within the body.

View Article and Find Full Text PDF

The curious case of mitochondrial sirtuin in rewiring breast cancer metabolism: Mr Hyde or Dr Jekyll?

Biochim Biophys Acta Mol Basis Dis

January 2025

Department of Public Health Genomics, Centre for DNA Repair and Genome Stability (CDRGS), Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India. Electronic address:

Mammalian sirtuins are class III histone deacetylases involved in the regulation of multiple biological processes including senescence, DNA repair, apoptosis, proliferation, caloric restriction, and metabolism. Among the mammalian sirtuins, SIRT3, SIRT4, and SIRT5 are localized in the mitochondria and collectively termed the mitochondrial sirtuins. Mitochondrial sirtuins are NAD+-dependent deacetylases that play a central role in cellular metabolism and function as epigenetic regulators by performing post-translational modification of cellular proteins.

View Article and Find Full Text PDF

Multiple sclerosis (MS) is a prevalent inflammatory neurodegenerative disease in young people, causing neurological abnormalities and impairment. To investigate a novel therapeutic agent for MS, we observed the impact of maresin 1 (MaR1) on disease progression in a well-known, relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) mouse model. Treatment with MaR1 accelerated inflammation resolution, reduced neurological impairment, and delayed disease development by reducing immune cell infiltration (CD4+IL-17+ and CD4+IFNγ+) into the central nervous system (CNS).

View Article and Find Full Text PDF

Metabolic Reprogramming of Neutrophils in the Tumor Microenvironment: Emerging Therapeutic Targets.

Cancer Lett

January 2025

Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200025, China. Electronic address:

Neutrophils are pivotal in the immune system and have been recognized as significant contributors to cancer development and progression. These cells undergo metabolic reprogramming in response to various stimulus, including infections, diseases, and the tumor microenvironment (TME). Under normal conditions, neutrophils primarily rely on aerobic glucose metabolism for energy production.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!