Mini review: The FDA-approved prescription drugs that target the MAPK signaling pathway in women with breast cancer

Breast cancer (BC) is the most common cancer and the prevalent type of malignancy among women. Multiple risk factors, including genetic changes, biological age, dense breast tissue, and obesity are associated with BC. The mitogen-activated protein kinases (MAPK) signaling pathway has a pivotal role in regulating biological functions such as cell proliferation, differentiation, apoptosis, and survival. It has become evident that the MAPK pathway is associated with tumorigenesis and may promote breast cancer development. The MAPK/RAS/RAF cascade is closely associated with breast cancer. RAS signaling can enhance BC cell growth and progression. B-Raf is an important kinase and a potent RAF isoform involved in breast tumor initiation and differentiation. Depending on the reasons for cancer, there are different strategies for treatment of women with BC. Till now, several FDA-approved treatments have been investigated that inhibit the MAPK pathway and reduce metastatic progression in breast cancer. The most common breast cancer drugs that regulate or inhibit the MAPK pathway may include Farnesyltransferase inhibitors (FTIs), Sorafenib, Vemurafenib, PLX8394, Dabrafenib, Ulixertinib, Simvastatin, Alisertib, and Teriflunomide. In this review, we will discuss the roles of the MAPK/RAS/RAF/MEK/ERK pathway in BC and summarize the FDA-approved prescription drugs that target the MAPK signaling pathway in women with BC.

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Anti-Breast Cancer Effect of 2-Dodecyl-6-Methoxycyclohexa-2,5-Diene-1,4-Dione in vivo and in vitro Through MAPK Signaling Pathway

Drug Design Development and Therapy ◽

10.2147/dddt.s237699 ◽

2020 ◽

Vol Volume 14 ◽

pp. 2667-2684 ◽

Cited By ~ 1

Author(s):

Xing Zhou ◽

Xingchun Wu ◽

Luhui Qin ◽

Shunyu Lu ◽

Hongliang Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Mapk Signaling ◽

Mapk Signaling Pathway

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miR-3188 Regulates Cell Proliferation, Apoptosis, and Migration in Breast Cancer by Targeting TUSC5 and Regulating the p38 MAPK Signaling Pathway

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504017x14953948675421 ◽

2018 ◽

Vol 26 (3) ◽

pp. 363-372 ◽

Cited By ~ 11

Author(s):

Xiaowen Chen ◽

Jianli Chen

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Signaling Pathway ◽

P38 Mapk ◽

Molecular Mechanisms ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Luciferase Reporter ◽

And Migration ◽

Mcf 7

This study intended to investigate the effects of miR-3188 on breast cancer and to reveal the possible molecular mechanisms. miR-3188 was upregulated and TUSC5 was downregulated in breast cancer tissues and MCF-7 cells compared to normal tissue and MCF-10 cells. After MCF-7 cells were transfected with miR-3188 inhibitor, cell proliferation and migration were inhibited, whereas apoptosis was promoted. Luciferase reporter assay suggested that TUSC5 was a target gene of miR-3188. In addition, miR-3188 overexpression increased the p-p38 expression, while miR-3188 suppression decreased the p-p38 expression significantly. miR-3188 regulated breast cancer progression via the p38 MAPK signaling pathway. In conclusion, miR-3188 affects breast cancer cell proliferation, apoptosis, and migration by targeting TUSC5 and activating the p38 MAPK signaling pathway. miR-3188 may serve as a potential therapeutic agent for the treatment of breast cancer.

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Estrogen Enhances Matrix Synthesis in Nucleus Pulposus Cell through the Estrogen Receptor β-p38 MAPK Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000447915 ◽

2016 ◽

Vol 39 (6) ◽

pp. 2216-2226 ◽

Cited By ~ 11

Author(s):

Pei Li ◽

Yuan Xu ◽

Yibo Gan ◽

Liyuan Wang ◽

Bin Ouyang ◽

...

Keyword(s):

Estrogen Receptor ◽

Signaling Pathway ◽

P38 Mapk ◽

Mapk Pathway ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Matrix Synthesis ◽

P38 Mapk Pathway ◽

Collagen Ii

Background/Aims: Matrix homeostasis within the disc nucleus pulposus (NP) tissue is important for disc function. Increasing evidence indicates that sex hormone can influence the severity of disc degeneration. This study was aimed to study the role of 17β-estradiol (E2) in NP matrix synthesis and its underlying mechanism. Methods: Rat NP cells were cultured with (10-5, 10-7 and 10-9 M) or without (control) E2 for48 hours. The estrogen receptor (ER)-β antagonist PHTPP and ERβ agonist ERB 041 were used to investigate the role mediated by ERβ. The p38 MAPK inhibitor SB203580 was used to investigate the role of p38 MAPK signaling pathway. Gene and protein expression of SOX9, aggrecan and collagen II, glycosaminoglycan (GAG) content, and immunostaining assay for aggrecan and collagen II were analyzed to evaluate matrix production in rat NP cells. Results: E2 enhanced NP matrix synthesis in a concentration-dependent manner regarding gene and proetin expression of SOX9, aggrecan and collagen II, protein deposition of aggrecan and collagen II, and GAG content. Moreover, activation of p38 MAPK signaling pathway was increased with elevating E2 concentration. Further analysis indicated that ERB 041 and PHTPP could respectively enhance and suppress effects of E2 on matrix synthesis in NP cells, as well as activation of p38 MAPK pathway. Additionally, inhibition of p38 MAPK signaling pathway significantly abolished the effects of E2 on matrix synthesis. Conclusion: E2 can enhance matrix synthesis of NP cells and the ERβ/p38 MAPK pathway is involved in this regulatory process.

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Long noncoding RNA 00976 promotes pancreatic cancer progression through OTUD7B by sponging miR-137 involving EGFR/MAPK pathway

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1388-4 ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 10

Author(s):

Shan Lei ◽

Zhiwei He ◽

Tengxiang Chen ◽

Xingjun Guo ◽

Zhirui Zeng ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Signaling Pathway ◽

Mapk Pathway ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Migration And Invasion ◽

Potential Biomarker

Abstract Background Accumulation evidence indicates the vital role of long non-coding RNAs (lncRNAs) in tumorigenesis and the progression of malignant tumors, including pancreatic cancer (PC). However, the role and the molecular mechanism of long non-coding RNA 00976 is unclear in pancreatic cancer. Methods In situ hybridization (ISH) and qRT-PCR was performed to investigate the association between linc00976 expression and the clinicopathological characteristics and prognosis of patients with PC. Subsequently, linc00976 over-expression vector and shRNAs were transfected into PC cells to up-regulate or down-regulate linc00976 expression. Loss- and gain-of function assays were performed to investigate the role of linc00976 in proliferation and metastasis in vitro and vivo. ITRAQ, bioinformatic analysis and rescue assay were used to illustrate the ceRNA mechanism network of linc00976/miR-137/OTUD7B and its downstream EGFR/MAPK signaling pathway. Results linc00976 expression was overexpressed in PC tissues and cell lines and was positively associated with poorer survival in patients with PC. Function studies revealed that linc00976 knockdown significantly suppressed cell proliferation, migration and invasion in vivo and in vitro, whereas its overexpression reversed these effects. Based on Itraq results and online database prediction, Ovarian tumor proteases OTUD7B was found as a downstream gene of linc00976, which deubiquitinated EGFR mediates MAPK signaling activation. Furthermore, Bioinformatics analysis and luciferase assays and rescue experiments revealed that linc00976/miR137/OTUD7B established the ceRNA network modulating PC cell proliferation and tumor growth. Conclusion The present study demonstrates that linc00976 enhances the proliferation and invasion ability of PC cells by upregulating OTUD7B expression, which was a target of miR-137. Ultimately, OTUD7B mediates EGFR and MAPK signaling pathway, suggesting that linc00976/miR-137/OTUD7B/EGFR axis may act as a potential biomarker and therapeutic target for PC.

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LncRNA LIPE-AS1 Predicts Poor Survival of Cervical Cancer and Promotes Its Proliferation and Migration via Modulating miR-195-5p/MAPK Pathway

Frontiers in Oncology ◽

10.3389/fonc.2021.639980 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jie Zhang ◽

Pinping Jiang ◽

Shoyu Wang ◽

Wenjun Cheng ◽

Shilong Fu

Keyword(s):

Cervical Cancer ◽

Western Blot ◽

Signaling Pathway ◽

Mapk Pathway ◽

Mapk Signaling ◽

Tumor Formation ◽

Mapk Signaling Pathway ◽

Rt Pcr ◽

Mesenchymal Transformation

Aims: A growing number of studies have unveiled that long non-coding RNA (lncRNA) is conductive to cervical cancer (CC) development. However, the effect of LIPE-AS1 is remained to be studied in CC.Main Methods: Reverse transcription-polymerase chain reaction (RT-PCR) was employed to measure LIPE-AS1 expression in CC tissues and the adjacent normal tissues. Additionally, we conducted gain- and loss-of functional experiments of LIPE-AS1 and adopted CCK8 assay, BrdU assay, and in vivo tumor formation experiment to test the proliferation of CC cells (HCC94 and HeLa). Besides, the apoptosis, invasion, and epithelial-mesenchymal transformation (EMT) of CC cells were estimated using flow cytometry, transwell assay, and western blot, respectively. Further, LIPE-AS1 downstream targets were analyzed through bioinformatics, and the binding relationships between LIPE-AS1 and miR-195-5p were verified via dual-luciferase activity experiment and RNA Protein Immunoprecipitation (RIP) assay. Moreover, rescue experiments were conducted to confirm the effects of LIPE-AS1 and miR-195-5p in regulating CC development and the expressions of MAPK signaling pathway related proteins were detected by RT-PCR, western blot, and immunofluorescence.Key Findings: LIPE-AS1 was over-expressed in CC tissues (compared to normal adjacent tissues) and was notably related to tumor volume, distant metastasis. Overexpressing LIPE-AS1 accelerated CC cell proliferation, migration and EMT, inhibited apoptosis; while LIPE-AS1 knockdown had the opposite effects. The mechanism studies confirmed that LIPE-AS1 sponges miR-195-5p as a competitive endogenous RNA (ceRNA), which targets the 3′-untranslated region (3′-UTR) of MAP3K8. LIPE-AS1 promoted the expression of MAP3K8 and enhanced ERK1/2 phosphorylation, which were reversed by miR-195-5p.Significance: LIPE-AS1 regulates CC progression through the miR-195-5p/MAPK signaling pathway, providing new hope for CC diagnosis and treatment.

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Cardiovascular protective effects of GLP-1:A focus on the MAPK signaling pathway

Biochemistry and Cell Biology ◽

10.1139/bcb-2021-0365 ◽

2021 ◽

Author(s):

Yu-Yan Zhao ◽

Lin-Hui Chen ◽

Liang Huang ◽

Yong-Zhen Li ◽

Chen Yang ◽

...

Keyword(s):

Signaling Pathway ◽

Metabolic Diseases ◽

Mapk Pathway ◽

Signal Transduction Pathway ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Mitogen Activated Protein Kinase ◽

Protective Effects ◽

Glucagon Like Peptide 1 ◽

Common Signal

Cardiovascular and related metabolic diseases are significant global health challenges. Glucagon-like peptide 1 (GLP-1) is a brain-gut peptide secreted by ileal endocrine that is now an established drug target in type 2 diabetes (T2DM). GLP-1 targeting agents have been shown not only to treat T2DM, but also to exert cardiovascular protective effects through regulating multiple signaling pathways. The mitogen-activated protein kinase (MAPK) pathway, a common signal transduction pathway for transmitting extracellular signals to downstream effector molecules, is involved in regulating diverse cell physiological processes, including cell proliferation, differentiation, stress, inflammation, functional synchronization, transformation and apoptosis. The purpose of this review is to highlight the relationship between GLP-1 and cardiovascular disease (CVD), and discuss how GLP-1 exerts cardiovascular protective effects through MAPK signaling pathway. This review also discusses the future challenges in fully characterizing and evaluating the CVD protective effects of GLP-1 receptor agonists (GLP-1RA) at the cellular and molecular level. A better understanding of MAPK signaling pathway that are disregulated in CVD may aid in the design and development of promising GLP-1RA.

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