DCZ0415, a small‐molecule inhibitor targeting TRIP13, inhibits EMT and metastasis via inactivation of the FGFR4/STAT3 axis and the Wnt/β‐catenin pathway in colorectal cancer

Agarwal, Sumit; Afaq, Farrukh; Bajpai, Prachi; Kim, Hyung‐Gyoon; Elkholy, Amr; Behring, Michael; Chandrashekar, Darshan S.; Diffalha, Sameer Al; Khushman, Moh’d; Sugandha, Shajan P.; Varambally, Sooryanarayana; Manne, Upender

doi:10.1002/1878-0261.13201

Cited by 34 publications

(25 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Overexpression of GOLT1B can increase the level of DVL2 and enhance its plasma membrane translocation, then activate the downstream Wnt/β-catenin pathway and increase the level of nuclear β-catenin, thereby inducing epithelial-mesenchymal transition (EMT) [ 112 ]. DCZ0415, a small molecule inhibitor against TRIP13, inhibits EMT and metastasis in colorectal cancer by inactivating the FGFR4/STAT3 axis and the Wnt/β-catenin pathway [ 113 ].…”

Section: Wnt Pathway-related Biochemical Processmentioning

confidence: 99%

Wnt signaling in colorectal cancer: pathogenic role and therapeutic target

et al. 2022

View full text Add to dashboard Cite

Background The Wnt signaling pathway is a complex network of protein interactions that functions most commonly in embryonic development and cancer, but is also involved in normal physiological processes in adults. The canonical Wnt signaling pathway regulates cell pluripotency and determines the differentiation fate of cells during development. The canonical Wnt signaling pathway (also known as the Wnt/β-catenin signaling pathway) is a recognized driver of colon cancer and one of the most representative signaling pathways. As a functional effector molecule of Wnt signaling, the modification and degradation of β-catenin are key events in the Wnt signaling pathway and the development and progression of colon cancer. Therefore, the Wnt signaling pathway plays an important role in the pathogenesis of diseases, especially the pathogenesis of colorectal cancer (CRC). Objective Inhibit the Wnt signaling pathway to explore the therapeutic targets of colorectal cancer. Methods Based on studying the Wnt pathway, master the biochemical processes related to the Wnt pathway, and analyze the relevant targets when drugs or inhibitors act on the Wnt pathway, to clarify the medication ideas of drugs or inhibitors for the treatment of diseases, especially colorectal cancer. Results Wnt signaling pathways include: Wnt/β-catenin or canonical Wnt signaling pathway, planar cell polarity (Wnt-PCP) pathway and Wnt-Ca2+ signaling pathway. The Wnt signaling pathway is closely related to cancer cell proliferation, stemness, apoptosis, autophagy, metabolism, inflammation and immunization, microenvironment, resistance, ion channel, heterogeneity, EMT/migration/invasion/metastasis. Drugs/phytochemicals and molecular preparations for the Wnt pathway of CRC treatment have now been developed. Wnt inhibitors are also commonly used clinically for the treatment of CRC. Conclusion The development of drugs/phytochemicals and molecular inhibitors targeting the Wnt pathway can effectively treat colorectal cancer clinically.

show abstract

Section: Wnt Pathway-related Biochemical Processmentioning

confidence: 99%

Wnt signaling in colorectal cancer: pathogenic role and therapeutic target

et al. 2022

View full text Add to dashboard Cite

show abstract

“…TRIP13 is implicated in EMT in lung cancer through modulation of TGF-β signaling (47,(57)(58)(59) . TRIP13 inhibition blocks EMT in colorectal cancer (46) and multiple myeloma (60) . TRIP13 modulates TGF-β-SMAD signaling in multiple disease states (57,58) , and is itself a target of TGF-β signaling in mice (63) .…”

Section: Discussionmentioning

confidence: 99%

“…Upregulation of TRIP13 has been shown to promote EMT in cancer cells (45)(46)(47) and IPF AT2 cells express higher levels of mesenchymal proteins (48)(49)(50) . We hypothesized that in IPF, TRIP13 promotes AT2 cell acquisition of mesenchymal features.…”

Section: Trip13 Is Increased In Ipf Tissues and At2 Cellsmentioning

confidence: 99%

Integrated multiomic analysis identifiesTRIP13as a mediator of alveolar epithelial type II cell dysfunction in idiopathic pulmonary fibrosis

St. Pierre,

Berhan,

Sung

et al. 2024

Preprint

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive lung disease urgently needing new therapies. Current treatments only delay disease progression, leaving lung transplant as the sole remaining option. Recent studies support a model whereby IPF arises because alveolar epithelial type II (AT2) cells, which normally mediate distal lung regeneration, acquire airway and/or mesenchymal characteristics, preventing proper repair. Mechanisms driving this abnormal differentiation remain unclear. We performed integrated transcriptomic and epigenomic analysis of purified AT2 cells which revealed genome-wide alterations in IPF lungs. The most prominent epigenetic alteration was activation of an enhancer in thyroid receptor interactor 13 (TRIP13), coinciding with TRIP13 upregulation. TRIP13 is broadly implicated in epithelial-mesenchymal plasticity and transforming growth factor-beta; signaling. In cultured human AT2 cells and lung slices, small molecule TRIP inhibitor DCZ0415 prevented acquisition of the mesenchymal gene signature characteristic of IPF, suggesting TRIP13 inhibition as a potential therapeutic approach to fibrotic disease.

show abstract

“…In the other side, c-Myc was able to induce the transcription of TRIP13[8, 12,34]. Recent discoveries have revealed that TRIP13 regulated the Wnt signaling pathway and the epithelial-mesenchymal transition in cervical cancer [35], lung cancer[36], thyroid cancer [37], colorectal cancer [32], cholangiocarcinoma[8], which could induce tumor growth and progression. While researches on TRIP13 develop fast, the prognostic value of TRIP13 in cancer is still uncertain.…”

Section: Discussionmentioning

confidence: 99%

“…TRIP13overexpressing cancer cells showed a signi cant increase in proliferation, invasion, and migration compared with control cells, on the contrary, depletion of TRIP13 by shRNA or TRIP13 inhibitor DCZ0415 could signi cantly inhibit cancer cell growth, induce cell apoptosis and enhance drug sensitivity [7,12,31]. Agarwal S et al have demonstrated that TRIP13 interacted with FGFR4 which could activate the EGFR-AKT pathway in colorectal cancer [11,32]. In addition, Gao Y et al have found that TRIP13 is directly bound to EGFR and modulated the EGFR signaling pathway in bladder cancer [19].…”

Section: Discussionmentioning

confidence: 99%

TRIP13 as a prognostic marker and its correlation with clinicopathological features in human cancers: a meta-analysis

Ji-pin

Deng

Xiao

et al. 2022

Preprint

View full text Add to dashboard Cite

Background: Recent studies have shown thyroid hormone receptor interacting protein 13 (TRIP13) is involved in tumorigenesis and associated with poor clinical outcomes. Here, we conducted a meta-analysis to assess the effect of TRIP13 expression on clinicopathological features and prognosis in patients with different kinds of cancers. Methods: The comprehensive literature search was performed through the PubMed, Embase, and Web of Science electronic databases to identify eligible studies. The pooled hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI) were calculated by STATA 15.0 software to evaluate the correlation between TRIP13 with overall survival (OS) and clinicopathology. Results: In total, 1461 patients from 12 studies were included in this meta-analysis. The pooled results suggested that high expression of TRIP13 correlated to unfavorable OS (HR=1.91, 95%CI 1.67-2.16, P<0.001) with no heterogeneity (I2=0.0, P=0.975). Subgroup analysis also indicated a significant association between high TRIP13 expression and poor OS regardless of tumor type, sample size, or method of data extraction. Moreover, a high level of TRIP13 was positively associated with tumor invasion depth (OR=2.86, 95%CI 1.38-5.94), lymph node metastasis (OR=3.72, 95%CI 2.65-5.20), distant metastasis (OR=2.64, 95%CI 1.42-4.91), and advanced TNM stage (OR=2.57, 95%CI 1.87-3.53) in patients with cancers. Conclusion: High expression of TRIP13 has a significant correlation with poor clinical outcomes and could serve as an unfavorable prognostic biomarker in cancer patients.

show abstract

DCZ0415, a small‐molecule inhibitor targeting TRIP13, inhibits EMT and metastasis via inactivation of the FGFR4/STAT3 axis and the Wnt/β‐catenin pathway in colorectal cancer

Cited by 34 publications

References 59 publications

Wnt signaling in colorectal cancer: pathogenic role and therapeutic target

Wnt signaling in colorectal cancer: pathogenic role and therapeutic target

Integrated multiomic analysis identifiesTRIP13as a mediator of alveolar epithelial type II cell dysfunction in idiopathic pulmonary fibrosis

TRIP13 as a prognostic marker and its correlation with clinicopathological features in human cancers: a meta-analysis

Contact Info

Product

Resources

About