The tyrosine phosphatase SHP2 promotes proliferation and oxaliplatin resistance of colon cancer cells through AKT and ERK

Yu, Mengchao; Xu, Chengzhen; Zhang, Hongwei; Lun, Jie; Wang, Lei; Zhang, Gang; Fang, Jing

doi:10.1016/j.bbrc.2021.05.068

Cited by 13 publications

(6 citation statements)

References 27 publications

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“…Although oxaliplatin is very effective for cancers in the initial period, the resistance occurs eventually. Mechanisms of the resistance include the induction of multidrug resistance efflux transporter, ABCG2 (Hsu et al, 2018), YTH m6A RNA‐binding protein 3 (YTHDF3) (Zhao et al, 2022), and SH2 domain‐containing phosphatase 2 (Yu et al, 2021). Ech exhibited similar cytotoxicity and induced apoptosis in both oxaliplatin‐sensitive and ‐resistance cells (Figures 1 and 3).…”

Section: Discussionmentioning

confidence: 99%

Echinatin induces reactive oxygen species‐mediated apoptosis via JNK/p38 MAPK signaling pathway in colorectal cancer cells

Kwak

Lee

et al. 2022

Phytotherapy Research

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Colorectal cancer (CRC) is a very common and deadly cancer worldwide, and oxaliplatin is used as first‐line chemotherapy. However, resistance usually develops, limiting treatment. Echinatin (Ech) is the main component of licorice and exhibits various therapeutic effects on inflammation‐mediated diseases and cancer, ischemia/reperfusion, and liver injuries. The present study elucidated the underlying molecular mechanism of Ech‐induced apoptosis in both oxaliplatin‐sensitive (HT116 and HT29) and ‐resistant (HCT116‐OxR and HT29‐OxR) CRC cells. To evaluate the antiproliferative activities of Ech, we performed MTT and soft agar assays. Ech reduced viability, colony size, and numbers of CRC cells. The underlying molecular mechanisms were explored by various flow cytometry analyses. Ech‐induced annexin‐V stained cells, reactive oxygen species (ROS) generation, cell cycle arrest, JNK/p38 MAPK activation, endoplasmic reticulum (ER) stress, mitochondrial membrane potential depolarization, and multi‐caspase activity. In addition apoptosis‐, cell cycle‐, and ER stress‐related protein levels were confirmed by western blotting. Moreover, we verified ROS‐mediated cell death by treatment with inhibitors such as N‐acetyl‐L‐cysteine, SP600125, and SB203580. Taken together, Ech exhibits anticancer activity in oxaliplatin‐sensitive and ‐resistant CRCs by inducing ROS‐mediated apoptosis through the JNK/p38 MAPK signaling pathway. This is the first study to show that Ech has the potential to treat drug‐resistant CRC, providing new directions for therapeutic strategies targeting drug‐resistant CRC.

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Section: Discussionmentioning

confidence: 99%

Echinatin induces reactive oxygen species‐mediated apoptosis via JNK/p38 MAPK signaling pathway in colorectal cancer cells

Kwak

Lee

et al. 2022

Phytotherapy Research

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“…This evidence holds potential therapeutic promise in light of the beneficial effects of metformin as an anti-fibrotic mediator through AMPK activation [ 34 ]. Finally, it is also interesting that another mediator of cancer, SHP2, is a potential therapeutic target for pulmonary fibrosis [ 35 , 36 , 37 ]. Focusing on commonalities between cancer and pulmonary fibrosis might lead to novel anti-fibrotic compounds, similarly with the process of nintedanib repositioning [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

SH2 Domain-Containing Phosphatase-SHP2 Attenuates Fibrotic Responses through Negative Regulation of Mitochondrial Metabolism in Lung Fibroblasts

et al. 2023

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Background: We have previously shown that SHP2 downregulation may predispose fibroblasts to differentiate into myofibroblasts and proposed a role for SHP2 downregulation in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Recent data have shown that SHP2 localizes to the mitochondrial intercristae, and its overexpression enhances mitochondrial metabolism leading to oxidative stress and senescence. Objective: To determine the effect of SHP2 on fibrotic responses. Methods and Results: Primary mouse lung fibroblasts derived from mice carrying a conditional knock-in mutation (D61G/+), rendering the SHP2 catalytic domain constitutively active, had reduced proliferation (1.6-fold, p < 0.05), migration (2-fold, p < 0.05), as well as reduced responsiveness of TGFB-1 induced fibroblasts-to-myofibroblasts differentiation, compared to wild-type ones. Electron microscope analysis revealed that SHP2 D61G/+ mouse lung fibroblasts were characterized by mitochondrial abnormalities, including swollen mitochondria with disrupted electron-lucent cristae and an increased number of autophagosomes compared to wild-type ones. SHP2 D61G/+ MLFs exhibited increased protein levels of autophagy markers, including LC3B-II and p-62, evidence that was confirmed by immunofluorescence analysis. Mitochondrial function analysis revealed that stable (genotype D61G/+) overexpression of SHP2 led to impaired mitochondrial function, as assessed by decreased mitochondrial membrane potential (1.29-fold, p < 0.05), coupling efficiency (1.82 fold, p < 0.05), oxygen consumption rate (1.9-fold, p < 0.05), and increased reactive oxygen species production both at baseline (1.75-fold, p < 0.05) and following H2O2 stimulation (1.63-fold, p < 0.05) compared to wild-type ones (SHP2+/+). SHP2 D61G/+ mouse lung fibroblasts showed enhanced AMPK activity, as well as decreased activation of the mTORC1 signaling pathway, potentially leading to ineffective mitochondrial metabolism and increased autophagy. Conclusions: SHP2 attenuates fibrotic responses in fibroblast cell lines through negative regulation of mitochondrial metabolism and induction of autophagy. SHP2 activation may represent a promising therapeutic strategy for patients with fibrotic lung diseases.

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“…( 146 ) and Yu M et al. ( 147 ) demonstrated that PTPN11 promotes vascular growth and proliferation of colon cancer cells as well as resistance to oxaliplatin through AKT and Erk signaling pathways. However, Yuan H et al.…”

Section: Dual Role Of Ptpns In Specific Cancersmentioning

confidence: 99%

Critical roles of PTPN family members regulated by non-coding RNAs in tumorigenesis and immunotherapy

Tang

Qi²,

Zhou

et al. 2022

Front. Oncol.

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Since tyrosine phosphorylation is reversible and dynamic in vivo, the phosphorylation state of proteins is controlled by the opposing roles of protein tyrosine kinases (PTKs) and protein tyrosine phosphatase (PTPs), both of which perform critical roles in signal transduction. Of these, intracellular non-receptor PTPs (PTPNs), which belong to the largest class I cysteine PTP family, are essential for the regulation of a variety of biological processes, including but not limited to hematopoiesis, inflammatory response, immune system, and glucose homeostasis. Additionally, a substantial amount of PTPNs have been identified to hold crucial roles in tumorigenesis, progression, metastasis, and drug resistance, and inhibitors of PTPNs have promising applications due to striking efficacy in antitumor therapy. Hence, the aim of this review is to summarize the role played by PTPNs, including PTPN1/PTP1B, PTPN2/TC-PTP, PTPN3/PTP-H1, PTPN4/PTPMEG, PTPN6/SHP-1, PTPN9/PTPMEG2, PTPN11/SHP-2, PTPN12/PTP-PEST, PTPN13/PTPL1, PTPN14/PEZ, PTPN18/PTP-HSCF, PTPN22/LYP, and PTPN23/HD-PTP, in human cancer and immunotherapy and to comprehensively describe the molecular pathways in which they are implicated. Given the specific roles of PTPNs, identifying potential regulators of PTPNs is significant for understanding the mechanisms of antitumor therapy. Consequently, this work also provides a review on the role of non-coding RNAs (ncRNAs) in regulating PTPNs in tumorigenesis and progression, which may help us to find effective therapeutic agents for tumor therapy.

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The tyrosine phosphatase SHP2 promotes proliferation and oxaliplatin resistance of colon cancer cells through AKT and ERK

Cited by 13 publications

References 27 publications

Echinatin induces reactive oxygen species‐mediated apoptosis via JNK/p38 MAPK signaling pathway in colorectal cancer cells

Echinatin induces reactive oxygen species‐mediated apoptosis via JNK/p38 MAPK signaling pathway in colorectal cancer cells

SH2 Domain-Containing Phosphatase-SHP2 Attenuates Fibrotic Responses through Negative Regulation of Mitochondrial Metabolism in Lung Fibroblasts

Critical roles of PTPN family members regulated by non-coding RNAs in tumorigenesis and immunotherapy

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