Natural compounds targeting YAP/TAZ axis in cancer: Current state of art and challenges

Pharmacological Research, Journal Year: 2024, Volume and Issue: 203, P. 107167 - 107167

Published: April 9, 2024

Cancer has become a burgeoning global healthcare concern marked by its exponential growth and significant economic ramifications. Though advancements in the treatment modalities have increased overall survival quality of life, there are no definite treatments for advanced stages this malady. Hence, understanding diseases etiologies underlying molecular complexities, will usher development innovative therapeutics. Recently, YAP/TAZ transcriptional regulation been immense interest due to their role development, tissue homeostasis oncogenic transformations. axis functions as coactivators within Hippo signaling cascade, exerting pivotal influence on processes such proliferation, regeneration, renewal. In cancer, YAP is overexpressed multiple tumor types associated with cancer stem cell attributes, chemoresistance, metastasis. Activation mirrors cellular "social" behavior, encompassing factors adhesion mechanical signals transmitted from structure surrounding extracellular matrix. Therefore, it presents vulnerability clogs tumors that could provide wide window therapeutic effectiveness. Natural compounds utilized extensively successful interventions management diverse chronic illnesses, including cancer. Owing capacity genes pathways, natural exhibit potential either adjuvant therapy or combination conventional options. review, we delineate nexus axis, present an alternate strategy target

Language: Английский

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Advances of targeting the YAP/TAZ-TEAD complex in the hippo pathway for the treatment of cancers

European Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 244, P. 114847 - 114847

Published: Oct. 13, 2022

Language: Английский

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Activation of the EGFR/PI3K/AKT pathway limits the efficacy of trametinib treatment in head and neck cancer

Molecular Oncology, Journal Year: 2023, Volume and Issue: 17(12), P. 2618 - 2636

Published: July 28, 2023

Blocking the mitogen-activated protein kinase (MAPK) pathway with MEK1/2 inhibitor trametinib has produced promising results in patients head and neck squamous cell carcinoma (HNSCC). In current study, we showed that treatment leads to overexpression activation of epidermal growth factor receptor (EGFR) HNSCC lines patient-derived xenografts. Knockdown EGFR improved efficacy both vitro vivo. Mechanistically, demonstrated trametinib-induced hyperactivates phosphatidylinositol 3-kinase (PI3K)/AKT pathway. vitro, blocking PI3K GDC-0941 (pictilisib), or BYL719 (alpelisib), prevented AKT hyperactivation enhanced a synergistic manner. vivo, combination superior antitumor vs. single agents, leading tumor arrest. We confirmed our findings syngeneic murine cancer line Taken together, show induces EGFR/PI3K/AKT; thus, EGFR/PI3K is required improve HNSCC.

Language: Английский

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Unraveling a novel hippo-associated immunological prognostic signature: The contribution of SERPINE1 in facilitating colorectal cancer progression via the notch signaling pathway

Genomics, Journal Year: 2024, Volume and Issue: 116(2), P. 110794 - 110794

Published: Jan. 14, 2024

Accumulating evidence demonstrated that Hippo signaling pathway is implicated in tumor initiation and progression. However, there have been limited studies on establishing signatures utilizing genes related to the evaluate prognosis clinical efficacy colorectal cancer (CRC) patients. pathway-associated with prognostic significance were identified TCGA database. Subsequently, a signature associated was constructed using Cox LASSO regression analyses. Survival analysis, ROC stratified analyses conducted appraise performance effect of our model. We also explored relationship between risk score immune microenvironment. Furthermore, GO GSEA performed for SERPINE1. Additional experiments illuminate underlying function possible mechanism SERPINE1 CRC cell proliferation migration. 58 differentially expressed CRC. Among them, five (PPP2CB, SERPINE1, WNT5A, TCF7L1, LEF1) selected establish Multivariate analysis this exhibited excellent diagnostic performance, providing maximum benefits In accordance signatures, cases divided into low-risk high-risk groups. Remarkably, group displayed lower scores, reduced infiltration, decreased expression checkpoints. Low-risk could more possibly benefit from conventional chemotherapeutic targeted therapies. significantly elevated which linked worst overall survival. Moreover, inhibition suppressed proliferation, invasion, migration cells via Notch pathway. To sum up, we established novel immunological This offers accurate prediction can guide individualized therapy patients

Language: Английский

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Reactivating Hippo by Drug Compounds to Suppress Gastric Cancer and Enhance Chemotherapy Sensitivity

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(6), P. 107311 - 107311

Published: April 22, 2024

The Hippo signaling pathway plays an essential role in organ size control and tumorigenesis. Loss of signal hyper-activation the downstream oncogenic YAP are commonly observed various types cancers. We previously identified STRN3-containing PP2A phosphatase as a negative regulator MST1/2 kinases (i.e., Hippo) gastric cancer (GC), opening possibility selectively targeting PP2Aa-STRN3-MST1/2 axis to recover against cancer. Here, we further discovered 1) disulfiram (DSF), FDA-approved drug, which can similarly block binding STRN3 core enzyme 2) CX-6258 (CX), chemical inhibitor, that disrupt interaction between MST1/2, both allowing reactivation activity inhibit GC. More importantly, found these two compounds, via kinase-dependent manner, DNA repair sensitize GC towards chemotherapy. In addition, thiram, structural analog DSF, function cell proliferation or enhance chemotherapy sensitivity. Interestingly, inclusion copper ion enhanced such effects DSF thiram on treatment. Overall, this work demonstrated pharmacological by drug compounds potently for tumor

Language: Английский

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