Protein Tyrosine Phosphatases: Mechanisms in Cancer

Sivaganesh, Vignesh; Sivaganesh, Varsha; Scanlon, Christina Springstead; Iskander, Alexander; Maher, Salma; Le, Thu H.; Peethambaran, Bela

doi:10.3390/ijms222312865

Cited by 34 publications

(29 citation statements)

References 116 publications

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Section: Introductionmentioning

confidence: 99%

“…Abnormal expression of protein tyrosine phosphatases (PTPs) has been shown to be involved in numerous cancers [ 17 , 18 , 19 , 20 ]. PTPs could exert tumor suppressive functions via dephosphorylation of oncogenic proteins and promote cancer development and progression by positively regulating signaling pathways [ 19 , 20 ]. Protein tyrosine phosphatase receptor type O (PTPRO) is a member of PTPs, which phylogenetically belongs to a distinct branch of the tyrosine phosphatases.…”

Section: Introductionmentioning

confidence: 99%

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PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism

Dai

Xiang

Han

et al. 2022

Cancer Communications

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Background Abnormal expression of protein tyrosine phosphatases (PTPs) has been reported to be a crucial cause of cancer. As a member of PTPs, protein tyrosine phosphatase receptor type O (PTPRO) has been revealed to play tumor suppressive roles in several cancers, while its roles in colorectal cancer (CRC) remains to be elucidated. Hence, we aimed to explore the roles and mechanisms of PTPRO in CRC initiation and progression. Methods The influences of PTPRO on the growth and liver metastasis of CRC cells and the expression patterns of different lipid metabolism enzymes were evaluated in vitro and in vivo. Molecular and biological experiments were conducted to uncover the underpinning mechanisms of dysregulated de novo lipogenesis and fatty acid β‐oxidation. Results PTPRO expression was notably downregulated in CRC liver metastasis compared to the primary cancer, and such a downregulation was associated with poor prognosis of patients with CRC. PTPRO silencing significantly promoted cell growth and liver metastasis. Compared with PTPRO wild‐type mice, PTPRO‐knockout mice developed more tumors and harbored larger tumor loads under treatment with azoxymethane and dextran sulfate sodium. Gene set enrichment analysis revealed that PTPRO downregulation was significantly associated with the fatty acid metabolism pathways. Blockage of fatty acid synthesis abrogated the effects of PTPRO silencing on cell growth and liver metastasis. Further experiments indicated that PTPRO silencing induced the activation of the AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling axis, thus promoting de novo lipogenesis by enhancing the expression of sterol regulatory element‐binding protein 1 (SREBP1) and its target lipogenic enzyme acetyl‐CoA carboxylase alpha (ACC1) by activating the AKT/mTOR signaling pathway. Furthermore, PTPRO attenuation decreased the fatty acid oxidation rate by repressing the expression of peroxisome proliferator‐activated receptor alpha (PPARα) and its downstream enzyme peroxisomal acyl‐coenzyme A oxidase 1 (ACOX1) via activating the p38/extracellular signal‐regulated kinase (ERK) mitogen‐activated protein kinase (MAPK) signaling pathway. Conclusions PTPRO could suppress CRC development and metastasis via modulating the AKT/mTOR/SREBP1/ACC1 and MAPK/PPARα/ACOX1 pathways and reprogramming lipid metabolism.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism

Dai

Xiang

Han

et al. 2022

Cancer Communications

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“…For example, while a small amount of ROS may stimulate insulin receptor signaling, ROS generally cause insulin tolerance [25]. It is now well established that unregulated ROS signaling is the cause of aberrant cell growth and eventual tumor development or cellular senescence [26]. Excessive hydrogen peroxide causes hyperoxidation of the catalytic Cys and, beyond Cys-OH, results in the formation of Cys-sulfinic acid (Cys-SO 2 H) and further oxidized Cys-sulfonic acid (Cys-SO 3 H).…”

Section: Nadph Oxidasesmentioning

confidence: 99%

Superoxide Radicals in the Execution of Cell Death

2022

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Superoxide is a primary oxygen radical that is produced when an oxygen molecule receives one electron. Superoxide dismutase (SOD) plays a primary role in the cellular defense against an oxidative insult by ROS. However, the resulting hydrogen peroxide is still reactive and, in the presence of free ferrous iron, may produce hydroxyl radicals and exacerbate diseases. Polyunsaturated fatty acids are the preferred target of hydroxyl radicals. Ferroptosis, a type of necrotic cell death induced by lipid peroxides in the presence of free iron, has attracted considerable interest because of its role in the pathogenesis of many diseases. Radical electrons, namely those released from mitochondrial electron transfer complexes, and those produced by enzymatic reactions, such as lipoxygenases, appear to cause lipid peroxidation. While GPX4 is the most potent anti-ferroptotic enzyme that is known to reduce lipid peroxides to alcohols, other antioxidative enzymes are also indirectly involved in protection against ferroptosis. Moreover, several low molecular weight compounds that include α-tocopherol, ascorbate, and nitric oxide also efficiently neutralize radical electrons, thereby suppressing ferroptosis. The removal of radical electrons in the early stages is of primary importance in protecting against ferroptosis and other diseases that are related to oxidative stress.

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“…Protein tyrosine phosphatases (PTPs) play an essential role in many signal transduction pathways [2,10], and the identification of PTPs inhibitors can be a potential therapeutic target in the treatment of human diseases [1,10,11]. The most well-known inhibitors of PTPs are inorganic compounds, for example sodium orthovanadate [12,13], nitric oxide [14], or phenylarsine oxide [15].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, In Vitro, and Computational Studies of PTP1B Phosphatase Inhibitors Based on Oxovanadium(IV) and Dioxovanadium(V) Complexes

Kostrzewa

Jończyk

Drzeżdżon

et al. 2022

IJMS

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One of the main goals of recent bioinorganic chemistry studies has been to design and synthesize novel substances to treat human diseases. The promising compounds are metal-based and metal ion binding components such as vanadium-based compounds. The potential anticancer action of vanadium-based compounds is one of area of investigation in this field. In this study, we present five oxovanadium(IV) and dioxovanadium(V) complexes as potential PTP1B inhibitors with anticancer activity against the MCF-7 breast cancer cell line, the triple negative MDA-MB-231 breast cancer cell line, and the human keratinocyte HaCaT cell line. We observed that all tested compounds were effective inhibitors of PTP1B, which correlates with anticancer activity. [VO(dipic)(dmbipy)]·2 H2O (Compound 4) and [VOO(dipic)](2-phepyH)·H2O (Compound 5) possessed the greatest inhibitory effect, with IC50 185.4 ± 9.8 and 167.2 ± 8.0 nM, respectively. To obtain a better understanding of the relationship between the structure of the examined compounds and their activity, we performed a computer simulation of their binding inside the active site of PTP1B. We observed a stronger binding of complexes containing dipicolinic acid with PTP1B. Based on our simulations, we suggested that the studied complexes exert their activity by stabilizing the WPD-loop in an open position and limiting access to the P-loop.

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Protein Tyrosine Phosphatases: Mechanisms in Cancer

Cited by 34 publications

References 116 publications

PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism

PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism

Superoxide Radicals in the Execution of Cell Death

Synthesis, In Vitro, and Computational Studies of PTP1B Phosphatase Inhibitors Based on Oxovanadium(IV) and Dioxovanadium(V) Complexes

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