Doublecortin-like kinase 1 is a therapeutic target in squamous cell carcinoma.
Humans
Apoptosis
Carcinoma, Squamous Cell
/ drug therapy
Cell Line, Tumor
Doublecortin-Like Kinases
G2 Phase Cell Cycle Checkpoints
Head and Neck Neoplasms
Intracellular Signaling Peptides and Proteins
/ genetics
Protein Serine-Threonine Kinases
/ metabolism
Squamous Cell Carcinoma of Head and Neck
/ genetics
Animals
DCLK1
DiFiD
HNSCC
anal SCC
patient derived xenograft
therapy
Journal
Molecular carcinogenesis
ISSN: 1098-2744
Titre abrégé: Mol Carcinog
Pays: United States
ID NLM: 8811105
Informations de publication
Date de publication:
02 2023
02 2023
Historique:
revised:
19
09
2022
received:
30
08
2022
accepted:
27
09
2022
pmc-release:
01
02
2024
pubmed:
12
10
2022
medline:
21
1
2023
entrez:
11
10
2022
Statut:
ppublish
Résumé
Doublecortin like kinase 1 (DCLK1) plays a crucial role in several cancers including colon and pancreatic adenocarcinomas. However, its role in squamous cell carcinoma (SCC) remains unknown. To this end, we examined DCLK1 expression in head and neck SCC (HNSCC) and anal SCC (ASCC). We found that DCLK1 is elevated in patient SCC tissue, which correlated with cancer progression and poorer overall survival. Furthermore, DCLK1 expression is significantly elevated in human papilloma virus negative HNSCC, which are typically aggressive with poor responses to therapy. To understand the role of DCLK1 in tumorigenesis, we used specific shRNA to suppress DCLK1 expression. This significantly reduced tumor growth, spheroid formation, and migration of HNSCC cancer cells. To further the translational relevance of our studies, we sought to identify a selective DCLK1 inhibitor. Current attempts to target DCLK1 using pharmacologic approaches have relied on nonspecific suppression of DCLK1 kinase activity. Here, we demonstrate that DiFiD (3,5-bis [2,4-difluorobenzylidene]-4-piperidone) binds to DCLK1 with high selectivity. Moreover, DiFiD mediated suppression of DCLK1 led to G2/M arrest and apoptosis and significantly suppressed tumor growth of HNSCC xenografts and ASCC patient derived xenografts, supporting that DCLK1 is critical for SCC growth.
Identifiants
pubmed: 36218231
doi: 10.1002/mc.23472
pmc: PMC9852063
mid: NIHMS1840557
doi:
Substances chimiques
3,5-bis(2,4-difluorobenzylidene)-4-piperidone
0
DCLK1 protein, human
EC 2.7.1.11
Doublecortin-Like Kinases
EC 2.7.1.11
Intracellular Signaling Peptides and Proteins
0
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
145-159Subventions
Organisme : NCI NIH HHS
ID : P30 CA168524
Pays : United States
Organisme : NCRR NIH HHS
ID : UL1 RR033179
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000001
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2022 Wiley Periodicals LLC.
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