CK1α-targeting inhibits primary and metastatic colorectal cancer  in vitro, ex vivo, in cell-line-derived and patient-derived tumor  xenograft mice models

Ren, Fupeng; Zhu, Jingwen; Li, Kesang; Cheng, Yiquan; Zhu, Xiyan

doi:10.21037/tcr.2020.02.13

Cited by 3 publications

(2 citation statements)

References 27 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While studies have shown enhanced CK1α expression in oncogenic RAS signaling ( 11 , 19 , 20 ), the underlying regulatory mechanisms remain poorly understood. We previously reported that the elevated CK1α protein abundance was not accompanied by a corresponding increase in its mRNA transcript level, indicating that CK1α is likely regulated by post-transcriptional or translational mechanisms ( 11 ).…”

Section: Resultsmentioning

confidence: 99%

SFPQ promotes RAS-mutant cancer cell growth by modulating 5′-UTR mediated translational control of CK1α

et al. 2022

View full text Add to dashboard Cite

Oncogenic mutations in the RAS family of small GTPases are commonly found in human cancers and they promote tumorigenesis by altering gene expression networks. We previously demonstrated that Casein Kinase 1α (CK1α), a member of the CK1 family of serine/threonine kinases, is post-transcriptionally upregulated by oncogenic RAS signaling. Here, we report that the CK1α mRNA contains an exceptionally long 5′-untranslated region (UTR) harbouring several translational control elements, implicating its involvement in translational regulation. We demonstrate that the CK1α 5′-UTR functions as an IRES element in HCT-116 colon cancer cells to promote cap-independent translation. Using tobramycin-affinity RNA-pulldown assays coupled with identification via mass spectrometry, we identified several CK1α 5′-UTR-binding proteins, including SFPQ. We show that RNA interference targeting SFPQ reduced CK1α protein abundance and partially blocked RAS-mutant colon cancer cell growth. Importantly, transcript and protein levels of SFPQ and other CK1α 5′-UTR-associated RNA-binding proteins (RBPs) are found to be elevated in early stages of RAS-mutant cancers, including colorectal and lung adenocarcinoma. Taken together, our study uncovers a previously unappreciated role of RBPs in promoting RAS-mutant cancer cell growth and their potential to serve as promising biomarkers as well as tractable therapeutic targets in cancers driven by oncogenic RAS.

show abstract

Section: Resultsmentioning

confidence: 99%

SFPQ promotes RAS-mutant cancer cell growth by modulating 5′-UTR mediated translational control of CK1α

et al. 2022

View full text Add to dashboard Cite

show abstract

“…CK1α may also be critically involved in tumor progression and be overexpressed in CRC (Ren et al 2020). This would in turn lead to the hypothesis that CK1 isoforms offer interesting targets to develop CK1 isoform inhibitors as novel effective therapeutic approaches to hijack tumors (Amaravadi 2015;Janovská et al 2020;Knippschild et al 2014;Liu et al 2019).…”

Section: Introductionmentioning

confidence: 99%

Casein Kinase-1-Alpha Inhibitor (D4476) Sensitizes Microsatellite Instable Colorectal Cancer Cells to 5-Fluorouracil via Authophagy Flux Inhibition

Siri

Behrouj

Dastghaib

et al. 2021

Arch. Immunol. Ther. Exp.

View full text Add to dashboard Cite

Adjuvant chemotherapy with 5-fluorouracil (5-FU) does not improve survival of patients suffering from a form of colorectal cancer (CRC) characterized by high level of microsatellite instability (MSI-H). Given the importance of autophagy and multi-drug-resistant (MDR) proteins in chemotherapy resistance, as well as the role of casein kinase 1-alpha (CK1α) in the regulation of autophagy, we tested the combined effect of 5-FU and CK1α inhibitor (D4476) on HCT116 cells as a model of MSI-H colorectal cancer. To achieve this goal, the gene expression of Beclin1 and MDR genes, ABCG2 and ABCC3 were analyzed using quantitative real-time polymerase chain reaction. We used immunoblotting to measure autophagy flux (LC3, p62) and flow cytometry to detect apoptosis. Our findings showed that combination treatment with 5-FU and D4476 inhibited autophagy flux. Moreover, 5-FU and D4476 combination therapy induced G2, S and G1 phase arrests and it depleted mRNA of both cell proliferation-related genes and MDR-related genes (ABCG2, cyclin D1 and c-myc). Hence, our data indicates that targeting of CK1α may increase the sensitivity of HCT116 cells to 5-FU. To our knowledge, this is the first description of sensitization of CRC cells to 5-FU chemotherapy by CK1α inhibitor. Graphic abstract

show abstract

Casein kinase 1α 1 is involved in the progression of glioblastoma through HIF-1α-mediated autophagy

Nie

Liu

et al. 2022

Journal of Neurophysiology

View full text Add to dashboard Cite

Glioblastoma (GBM) is a malignant tumor prone to recurrence and resistant to conventional therapies. GBM cells show high autophagy activity, contributing to its rapid progression. Casein kinase 1 family, such as Casein kinase 1α (CK1α), has shown its effect on autophagy by binding to the hypoxia-inducible factor-1α (HIF-1α). This study investigates the expression of CK1α and HIF-1α in healthy and GBM tissues and its relations with autophagy-related genes and GBM cell viability. The expressions of CK1α, HIF-1α, and autophagy-related proteins in normal tissues, GBM tissues, and GBM cell lines (U87MG, U251, U118-MG, LN229, SHG44) were analyzed by qRT-PCR and Western blotting. In vitro, the U87MG cell line was transfected with pcDNA3.1-CK1α to enhance the expression of CK1α or both pcDNA3.1-CK1α and siRNA-HIF-1α. The expression of CK1α, HIF-1α, and autophagy-related proteins in GBM brain tissues and cell lines was higher than in normal brain tissues. In U87MG cells, enhanced CK1α expression upregulated the expression of HIF-1α and autophagy-related proteins and promoted cell proliferation. Inhibiting the expression of HIF-1α reduced the expression of autophagy-related proteins and decreased U87MG cell viability. Overexpressed CK1α positively regulates autophagy activity through the HIF-1α pathway. Inhibition of CK1α might be a potential therapeutic approach for glioblastoma therapy.

show abstract

CK1α-targeting inhibits primary and metastatic colorectal cancer in vitro, ex vivo, in cell-line-derived and patient-derived tumor xenograft mice models

Cited by 3 publications

References 27 publications

SFPQ promotes RAS-mutant cancer cell growth by modulating 5′-UTR mediated translational control of CK1α

SFPQ promotes RAS-mutant cancer cell growth by modulating 5′-UTR mediated translational control of CK1α

Casein Kinase-1-Alpha Inhibitor (D4476) Sensitizes Microsatellite Instable Colorectal Cancer Cells to 5-Fluorouracil via Authophagy Flux Inhibition

Casein kinase 1α 1 is involved in the progression of glioblastoma through HIF-1α-mediated autophagy

Contact Info

Product

Resources

About