DCLK1 and its interaction partners: An effective therapeutic target for colorectal cancer (Review)

Vijai, Muthu; Baba, Mursaleen; Ramalingam, Satish; Thiyagaraj, Anand

doi:10.3892/ol.2021.13111

Cited by 13 publications

(8 citation statements)

References 95 publications

(105 reference statements)

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“…The vast majority of these studies to date have focused on expression of DCLK1, which promotes tumor invasiveness, epithelial-to-mesenchymal transition (EMT), and metastasis (118,120,121). DCLK1 can drive numerous signaling cascades critical in EMT and is associated with negative clinical outcomes in cancer (122). Although an excellent marker for tuft cells in mice, DCLK1 alone is insufficient to infer tuft cell identity, particularly in humans (1).…”

Section: Injurymentioning

confidence: 99%

Tuft Cells: Context- and Tissue-Specific Programming for a Conserved Cell Lineage

Kotas

O’Leary

Locksley

2023

Annu. Rev. Pathol. Mech. Dis.

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Tuft cells are found in tissues with distinct stem cell compartments, tissue architecture, and luminal exposures but converge on a shared transcriptional program, including expression of taste transduction signaling pathways. Here, we summarize seminal and recent findings on tuft cells, focusing on major categories of function—instigation of type 2 cytokine responses, orchestration of antimicrobial responses, and emerging roles in tissue repair—and describe tuft cell–derived molecules used to affect these functional programs. We review what is known about the development of tuft cells from epithelial progenitors under homeostatic conditions and during disease. Finally, we discuss evidence that immature, or nascent, tuft cells with potential for diverse functions are driven toward dominant effector programs by tissue- or perturbation-specific contextual cues, which may result in heterogeneous mature tuft cell phenotypes both within and between tissues. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 18 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Section: Injurymentioning

confidence: 99%

Tuft Cells: Context- and Tissue-Specific Programming for a Conserved Cell Lineage

Kotas

O’Leary

Locksley

2023

Annu. Rev. Pathol. Mech. Dis.

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“…Many studies have shown that the overexpression of DCLK1 in cancer cells results in induction of EMT, stemness and increased cell migration and invasion, which can be reversed with small molecules targeting the kinase domain of DCLK1 [ 31 , 34 , 35 , 46 , 47 , 126 ]. In addition, targeting DCLK1 with anti-DCLK1 monoclonal antibody (CBT-15) or siRNAs showed promising results in reducing tumor burden, cancer stemness, invasion, and metastasis [ 31 , 35 , 41 , 46 , 47 , 48 , 49 , 50 , 51 , 54 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 ]. It remains to be shown whether such anti-DCLK1 targeting approaches are equally effective in the context of the various DCLK1 missense mutations that promote tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Structure-Guided Prediction of the Functional Impact of DCLK1 Mutations on Tumorigenesis

et al. 2023

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Doublecortin-like kinase 1 (DCLK1) is a functional serine/threonine (S/T)-kinase and a member of the doublecortin family of proteins which are characterized by their ability to bind to microtubules (MTs). DCLK1 is a proposed cancer driver gene, and its upregulation is associated with poor overall survival in several solid cancer types. However, how DCLK1 associates with MTs and how its kinase function contributes to pro-tumorigenic processes is poorly understood. This review builds on structural models to propose not only the specific functions of the domains but also attempts to predict the impact of individual somatic missense mutations on DCLK1 functions. Somatic missense mutations in DCLK1 are most frequently located within the N-terminal MT binding region and likely impact on the ability of DCLK1 to bind to αβ-tubulin and to polymerize and stabilize MTs. Moreover, the MT binding affinity of DCLK1 is negatively regulated by its auto-phosphorylation, and therefore mutations that affect kinase activity are predicted to indirectly alter MT dynamics. The emerging picture portrays DCLK1 as an MT-associated protein whose interactions with tubulin heterodimers and MTs are tightly controlled processes which, when disrupted, may confer pro-tumorigenic properties.

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“…It has been shown that down-regulation of NR5A2 is linked to worse overall survival of CRC patients [ 57 ]. The DCLK1 gene is reported to be up-regulated and associated with metastasis and prognosis in CRC [ 58 ]. Cytoplasmic expression of DCLK1-S, a novel DCLK1 isoform, has been shown to be associated with tumor aggressiveness and worse disease-specific survival in CRC [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

CpG Site-Based Signature Predicts Survival of Colorectal Cancer

Zhang

Kuchi

et al. 2022

Biomedicines

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Background: A critical unmet medical need in clinical management of colorectal cancer (CRC) pivots around lack of noninvasive and or minimally invasive techniques for early diagnosis and prognostic prediction of clinical outcomes. Because DNA methylation can capture the regulatory landscape of tumors and can be measured in body fluids, it provides unparalleled opportunities for the discovery of early diagnostic and prognostics markers predictive of clinical outcomes. Here we investigated use of DNA methylation for the discovery of potential clinically actionable diagnostic and prognostic markers for predicting survival in CRC. Methods: We analyzed DNA methylation patterns between tumor and control samples to discover signatures of CpG sites and genes associated with CRC and predictive of survival. We conducted functional analysis to identify molecular networks and signaling pathways driving clinical outcomes. Results: We discovered a signature of aberrantly methylated genes associated with CRC and a signature of thirteen (13) CpG sites predictive of survival. We discovered molecular networks and signaling pathways enriched for CpG sites likely to drive clinical outcomes. Conclusions: The investigation revealed that CpG sites can predict survival in CRC and that DNA methylation can capture the regulatory state of tumors through aberrantly methylated molecular networks and signaling pathways.

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DCLK1 and its interaction partners: An effective therapeutic target for colorectal cancer (Review)

Cited by 13 publications

References 95 publications

Tuft Cells: Context- and Tissue-Specific Programming for a Conserved Cell Lineage

Tuft Cells: Context- and Tissue-Specific Programming for a Conserved Cell Lineage

Structure-Guided Prediction of the Functional Impact of DCLK1 Mutations on Tumorigenesis

CpG Site-Based Signature Predicts Survival of Colorectal Cancer

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