Therapeutic Targeting of the NRF2 Signaling Pathway in Cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Telkoparan-Akillilar P
PROVIDER: S-EPMC7961421 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Many signaling pathways are dysregulated in cancer cells and the host tumor microenvironment. Aberrant receptor tyrosine kinase (RTK) pathways promote cancer development, progression, and metastasis. Hence, numerous therapeutic interventions targeting RTKs have been actively pursued. Axl is an RTK that belongs to the Tyro3, Axl, MerTK (TAM) subfamily. Axl binds to a high affinity ligand growth arrest specific 6 (Gas6) that belongs to the vitamin K-dependent family of proteins. The Gas6/Axl signaling pathway has been implicated to promote progression, metastasis, immune evasion, and therapeutic resistance in many cancer types. Therapeutic agents targeting Gas6 and Axl have been developed, and promising results have been observed in both preclinical and clinical settings when such agents are used alone or in combination therapy. This review examines the current state of therapeutics targeting the Gas6/Axl pathway in cancer and discusses Gas6- and Axl-targeting agents that have been evaluated preclinically and clinically.
| S-EPMC8469858 | biostudies-literature
Project description:The development and progression of cancer are associated with the dysregulation of multiple pathways involved in cell proliferation and survival, as well as dysfunction in redox balance, immune response, and inflammation. The master antioxidant pathway, known as the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, regulates the cellular defense against oxidative stress and inflammation, making it a promising cancer prevention and treatment target. Cannabinoids have demonstrated anti-tumor and anti-inflammatory properties, affecting signaling pathways, including Nrf2. Increased oxidative stress following exposure to anti-cancer therapy prompts cancer cells to activate antioxidant mechanisms. This indicates the dual effect of Nrf2 in cancer cells-influencing proliferation and apoptotic processes and protecting against the toxicity of anti-cancer therapy. Therefore, understanding the complex role of cannabinoids in modulating Nrf2 might shed light on its potential implementation as an anti-cancer support. In this review, we aim to highlight the impact of cannabinoids on Nrf2-related factors, with a focus on cancer prevention and treatment. Additionally, we have presented the results of several research studies that combined cannabidiol (CBD) with other compounds targeting Nrf2. Further studies should be directed toward exploring the anti-inflammatory effects of cannabinoids in the context of cancer prevention and therapy.
| S-EPMC10740807 | biostudies-literature
Project description:Molecular signaling pathways play a significant role in the regulation of biological mechanisms, and their abnormal expression can provide the conditions for cancer development. The signal transducer and activator of transcription 3 (STAT3) is a key member of the STAT proteins and its oncogene role in cancer has been shown. STAT3 is able to promote the proliferation and invasion of cancer cells and induces chemoresistance. Different downstream targets of STAT3 have been identified in cancer and it has also been shown that microRNA (miR), long non-coding RNA (lncRNA) and other molecular pathways are able to function as upstream mediators of STAT3 in cancer. In the present review, we focus on the role and regulation of STAT3 in gastric cancer (GC). miRs and lncRNAs are considered as potential upstream mediators of STAT3 and they are able to affect STAT3 expression in exerting their oncogene or onco-suppressor role in GC cells. Anti-tumor compounds suppress the STAT3 signaling pathway to restrict the proliferation and malignant behavior of GC cells. Other molecular pathways, such as sirtuin, stathmin and so on, can act as upstream mediators of STAT3 in GC. Notably, the components of the tumor microenvironment that are capable of targeting STAT3 in GC, such as fibroblasts and macrophages, are discussed in this review. Finally, we demonstrate that STAT3 can target oncogene factors to enhance the proliferation and metastasis of GC cells.
| S-EPMC7345582 | biostudies-literature
Project description:The Notch pathway plays a key role in several processes, including stem-cell self-renewal, proliferation, and cell differentiation. Several studies identified recurrent mutations in hematological malignancies making Notch one of the most desirable targets in leukemia and lymphoma. The Notch signaling mediates resistance to therapy and controls cancer stem cells supporting the development of on-target therapeutic strategies to improve patients' outcome. In this brief review, we outline the therapeutic potential of targeting Notch pathway in T-cell acute jlymphoblastic leukemia, chronic lymphocytic leukemia, and mantle cell lymphoma.
| S-EPMC6613627 | biostudies-literature
Project description:Clinical correlation studies have clearly shown that obesity is associated with breast cancer risk and patient survival. Although several potential mechanisms linking obesity and cancers have been proposed, the detailed molecular mechanism of obesity-mediated breast tumorigenesis has not yet been critically evaluated. In this study, we evaluated the effects of obesity on mammary tumor initiation and progression using mice with genetic and diet-induced obesity bearing mammary tumor xenografts and mouse mammary tumor virus-neu transgenic mice that were fed a high-fat diet. We show that obesity promoted mammary tumor growth and development in these animal models. Moreover, the expressions of TNF?, VEGF, IKK?, and mTOR are upregulated in mammary tumors of obese mice, suggesting that the IKK?/mTOR/VEGF signaling pathway is activated by TNF? in the tumors of obese mice. More importantly, inhibitors (rapamycin, bevacizumab, and aspirin) that target members of the pathway suppressed tumorigenesis and prolonged survival more effectively in obese mice than in nonobese mice. Here, we not only identified a specific signaling pathway that contributes to mammary tumorigenesis in obese mice but also a strategy for treating obesity-mediated breast cancer.
| S-EPMC3712288 | biostudies-other
Project description:The Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2 [Nrf2])-Keap1 (Kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1) signaling pathway is one of the most important cell defense and survival pathways. Nrf2 can protect cells and tissues from a variety of toxicants and carcinogens by increasing the expression of a number of cytoprotective genes. As a result, several Nrf2 activators are currently being tested as chemopreventive compounds in clinical trials. Just as Nrf2 protects normal cells, studies have shown that Nrf2 may also protect cancer cells from chemotherapeutic agents and facilitate cancer progression. Nrf2 is aberrantly accumulated in many types of cancer, and its expression is associated with a poor prognosis in patients. In addition, Nrf2 expression is induced during the course of drug resistance. Collectively, these studies suggest that Nrf2 contributes to both intrinsic and acquired chemoresistance. This discovery has opened up a broad spectrum of research geared toward a better understanding of the role of Nrf2 in cancer. This review provides an overview of (1) the Nrf2-Keap1 signaling pathway, (2) the dual role of Nrf2 in cancer, (3) the molecular basis of Nrf2 activation in cancer cells, and (4) the challenges in the development of Nrf2-based drugs for chemoprevention and chemotherapy.
| S-EPMC3814639 | biostudies-literature
Project description:Signal transducer and activator of transcription 3 (STAT3) is a critical transcription factor that has been firmly associated with colorectal cancer (CRC) initiation and development. STAT3 mediates key inflammatory mechanisms in colitis-associated cancer, becomes excessively activated in CRC, and enhances cancer cell proliferation, tumor growth, angiogenesis, invasion, and migration. STAT3 hyperactivation in malignant cells, surrounding immune cells and cancer-associated fibroblasts, mediates inhibition of the innate and adaptive immunity of the tumor microenvironment, and, therefore, tumor evasion from the immune system. These features highlight STAT3 as a promising therapeutic target; however, the mechanisms underlying these features have not been fully elucidated yet and STAT3 inhibitors have not reached the clinic in everyday practice. In the present article, we review the STAT3 signaling network in CRC and highlight the current notion for the design of STAT3-focused treatment approaches. We also discuss recent breakthroughs in combination immunotherapy regimens containing STAT3 inhibitors, therefore providing a new perception for the clinical application of STAT3 in CRC.
| S-EPMC8392110 | biostudies-literature
Project description:SUMOylation is a dynamic and reversible post-translational modification, characterized more than 20 years ago, that regulates protein function at multiple levels. Key oncoproteins and tumor suppressors are SUMO substrates. In addition to alterations in SUMO pathway activity due to conditions typically present in cancer, such as hypoxia, the SUMO machinery components are deregulated at the genomic level in cancer. The delicate balance between SUMOylation and deSUMOylation is regulated by SENP enzymes possessing SUMO-deconjugation activity. Dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to the tumorigenesis and drug resistance of various cancers in a context-dependent manner. Many molecular mechanisms relevant to the pathogenesis of specific cancers involve SUMO, highlighting the potential relevance of SUMO machinery components as therapeutic targets. Recent advances in the development of inhibitors targeting SUMOylation and deSUMOylation permit evaluation of the therapeutic potential of targeting the SUMO pathway in cancer. Finally, the first drug inhibiting SUMO pathway, TAK-981, is currently also being evaluated in clinical trials in cancer patients. Intriguingly, the inhibition of SUMOylation may also have the potential to activate the anti-tumor immune response. Here, we comprehensively and systematically review the recent developments in understanding the role of SUMOylation in cancer and specifically focus on elaborating the scientific rationale of targeting the SUMO pathway in different cancers.
| S-EPMC8431684 | biostudies-literature
Project description:The theory of cancer stem cells (CSCs) proposes that the different cells within a tumor, as well as metastasis deriving from it, are originated from a single subpopulation of cells with self-renewal and differentiation capacities. These cancer stem cells are supposed to be critical for tumor expansion and metastasis, tumor relapse and resistance to conventional therapies, such as chemo- and radiotherapy. The acquisition of these abilities has been attributed to the activation of alternative pathways, for instance, WNT, NOTCH, SHH, PI3K, Hippo, or NF-?B pathways, that regulate detoxification mechanisms; increase the metabolic rate; induce resistance to apoptotic, autophagic, and senescence pathways; promote the overexpression of drug transporter proteins; and activate specific stem cell transcription factors. The elimination of CSCs is an important goal in cancer therapeutic approaches because it could decrease relapses and metastatic dissemination, which are main causes of mortality in oncology patients. In this work, we discuss the role of these signaling pathways in CSCs along with their therapeutic potential.
| S-EPMC7479251 | biostudies-literature
Project description:The WNT signaling cascade is integral in numerous biological processes including embryonic development, cell cycle regulation, inflammation, and cancer. Hyperactivation of WNT signaling secondary to alterations to varying nodes of the pathway have been identified in multiple tumor types. These alterations converge into increased tumorigenicity, sustained proliferation, and enhanced metastatic potential. This review seeks to evaluate the evidence supporting the WNT pathway in cancer, the therapeutic strategies in modulating this pathway, and potential challenges in drug development.
| S-EPMC4591954 | biostudies-literature