DCLK1 as a Promising Marker for Radioresistance in Colorectal Cancer

Mohammadi, Chiman; Najafi, Rezvan

doi:10.1007/s12029-019-00292-z

Cited by 4 publications

(5 citation statements)

References 13 publications

(16 reference statements)

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“…Niclosamide is an FD-approved Wnt inhibitor that suppresses CSCs populations ( Park et al, 2019 ). Niclosamide, originally indicated for tapeworm infection, has anticancer effects in treating colorectal cancer, and DCLK1 inhibition might overcome radioresistance in CRC ( Wu et al, 2020a ; Mohammadi and Najafi 2020 ). Nintedanib inhibits VEGFR kinase activity, directly decreasing tumor growth and shrinkage ( Hilberg et al, 2018 ).…”

Section: Methods To Knockdown Dclk1mentioning

confidence: 99%

Pleiotropic effects of DCLK1 in cancer and cancer stem cells

Chhetri

Vengadassalapathy

Venkadassalapathy

et al. 2022

Front. Mol. Biosci.

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Doublecortin-like kinase 1 (DCLK1), a protein molecule, has been identified as a tumor stem cell marker in the cancer cells of gastrointestinal, pancreas, and human colon. DCLK1 expression in cancers, such as breast carcinoma, lung carcinoma, hepatic cell carcinoma, tuft cells, and human cholangiocarcinoma, has shown a way to target the DCLK1 gene and downregulate its expression. Several studies have discussed the inhibition of tumor cell proliferation along with neoplastic cell arrest when the DCLK1 gene, which is expressed in both cancer and normal cells, was targeted successfully. In addition, previous studies have shown that DCLK1 plays a vital role in various cancer metastases. The correlation of DCLK1 with numerous stem cell receptors, signaling pathways, and genes suggests its direct or an indirect role in promoting tumorigenesis. Moreover, the impact of DCLK1 was found to be related to the functioning of an oncogene. The downregulation of DCLK1 expression by using targeted strategies, such as embracing the use of siRNA, miRNA, CRISPR/Cas9 technology, nanomolecules, specific monoclonal antibodies, and silencing the pathways regulated by DCLK1, has shown promising results in both in vitro and in vivo studies on gastrointestinal (GI) cancers. In this review, we will discuss about the present understanding of DCLK1 and its role in the progression of GI cancer and metastasis.

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Section: Methods To Knockdown Dclk1mentioning

confidence: 99%

Pleiotropic effects of DCLK1 in cancer and cancer stem cells

Chhetri

Vengadassalapathy

Venkadassalapathy

et al. 2022

Front. Mol. Biosci.

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“…DCLK1 plays a critical role in injury response for repair via regulating DDR [8]. However, recently the role of DCLK1 in the regulation of DDR in cancers has established by many investigators [66][67][68]. In an in vitro mechanistic study, it is reported that DCLK1 caused chromatin instability, and chromatin rearrangement in colon, lung, and breast cancer cell lines, which drives the advancement of cancer cells for progression and this function is independent of its kinase activity [68].…”

Section: -[58])mentioning

confidence: 99%

DCLK1 and DNA Damage Response

Panneerselvam¹,

Qu²,

Houchen³

et al. 2021

Genotoxicity and Mutagenicity - Mechanisms and Test Methods

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Genome integrity is constantly monitored by sophisticated cellular networks, collectively termed as the DNA damage response (DDR). The DDR is a signaling network that includes cell cycle checkpoints and DNA repair and damage tolerance pathways. Failure of the DDR or associated events causes various diseases, including cancer. DDR is primarily mediated by phosphatidylinositol-3-kinase-like protein kinase (PIKKs) family members ataxia-telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related protein (ATR). However, one of the many unanswered questions regarding these signal-transduction pathways is: how does the cell turn the DDR signals on? There was no conclusive demonstration of the involvement of a specific sensory kinase in DDR signals until our recent research on the DCLK1 role in regulating ATM after genotoxic injury. Currently, various studies are demonstrating the importance of DCLK1 in DNA damage response. Here, we discuss the novel insights into the role of DCLK1 in DNA damage response.

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“…Therefore, DCLK1 probably is a potential therapeutic target to overcome chemoresistance. 42 However, the mechanisms of DCLK1-promoting chemoresistance remains not fully understood. Especially, the relationship between DCLK1, chemoresistance and tumour stem cells needs to be further clarified.…”

Section: Introductionmentioning

confidence: 99%

“…demonstrated that LRRK2‐IN‐1 (a nonspecific selective inhibitor of DCLK1) enhanced the cytotoxic effects of gemcitabine via suppressing Chk1 phosphorylation in pancreatic cancer cells. Therefore, DCLK1 probably is a potential therapeutic target to overcome chemoresistance 42 . However, the mechanisms of DCLK1‐promoting chemoresistance remains not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Targeting DCLK1 overcomes 5‐fluorouracil resistance in colorectal cancer through inhibiting CCAR1/β‐catenin pathway‐mediated cancer stemness

Wang

Zhao

Lin

et al. 2022

Clinical & Translational Med

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Background To date, 5‐fluorouracil‐based chemotherapy is very important for locally advanced or metastatic colorectal cancer (CRC). However, chemotherapy resistance results in tumor recurrence and metastasis, which is a major obstacle for treatment of CRC. Methods In the current research, we establish 5‐fluorouracil resistant cell lines and explore the potential targets associated with 5‐fluorouracil resistance in CRC. Moreover, we perform clinical specimen research, in vitro and in vivo experiments and molecular mechanism research, to reveal the biological effects and the mechanism of DCLK1 promoting 5‐fluorouracil resistance, and to clarify the potential clinical value of DCLK1 as a target of 5‐fluorouracil resistance in CRC. Results We discover that doublecortin‐like kinase 1 (DCLK1), a cancer stem cell maker, is correlated with 5‐fluorouracil resistance, and functionally promotes cancer stemness and 5‐fluorouracil resistance in CRC. Mechanistically, we elucidate that DCLK1 interacts with cell cycle and apoptosis regulator 1 (CCAR1) through the C‐terminal domain, and phosphorylates CCAR1 at the Ser343 site, which is essential for CCAR1 stabilisation. Moreover, we find that DCLK1 positively regulates β‐catenin signalling via CCAR1, which is responsible for maintaining cancer stemness. Subsequently, we prove that blocking β‐catenin inhibits DCLK1‐mediated 5‐fluorouracil resistance in CRC cells. Importantly, we demonstrate that DCLK1 inhibitor could block CCAR1/β‐catenin pathway‐mediated cancer stemness and consequently suppresses 5‐fluorouracil resistant CRC cells in vitro and in vivo. Conclusions Collectively, our findings reveal that DCLK1 promotes 5‐fluorouracil resistance in CRC by CCAR1/β‐catenin pathway‐mediated cancer stemness, and suggest that targeting DCLK1 might be a promising method to eliminate cancer stem cells for overcoming 5‐fluorouracil resistance in CRC.

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DCLK1 as a Promising Marker for Radioresistance in Colorectal Cancer

Abstract: Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Cited by 4 publications

References 13 publications

Pleiotropic effects of DCLK1 in cancer and cancer stem cells

Pleiotropic effects of DCLK1 in cancer and cancer stem cells

DCLK1 and DNA Damage Response

Targeting DCLK1 overcomes 5‐fluorouracil resistance in colorectal cancer through inhibiting CCAR1/β‐catenin pathway‐mediated cancer stemness

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