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ARTICLE
Exendin-4 inhibits the survival and invasiveness of two colorectal cancer cell lines via suppressing GS3Kβ/β-catenin/NF-κB axis through activating SIRT1
ATTALLA F. EL-KOTT1,2,*, AYMAN E. EL-KENAWY3, EMAN R. ELBEALY4, ALI S. ALSHEHRI1, HEBA S. KHALIFA2, MASHAEL MOHAMMED BIN-MEFERIJ5, EHAB E. MASSOUD6,7,8, AMIRA M. ALRAMLAWY9
1 Biology Department, College of Science, King Khalid University, Abha, 61413, Saudi Arabia
2 Zoology Department, College of Science, Damanhour University, Damanhour, 22511, Egypt
3 Pathology Department, College of Medicine, Taif University, Taif, 11099, Saudi Arabia
4 Biology Department, College of Science for Girls, King Khalid University, Abha, 61413, Saudi Arabia
5 Biology Department, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, 84428, Saudi Arabia
6 Biology Department, Faculty of Science and Arts, Dahran Aljnoub, King Khalid University, Abha, 61413, Saudi Arabia
7 Research Center for Advanced Materials Science, King Khalid University, Abha, 61413, Saudi Arabia
8 Agriculture Research Centre, Soil, Water and Environment Research Institute, Giza, 12619, Egypt
9 Mansoura Research Centre for Cord Stem Cell (MARC-CSC), Stem Cells Bank, Children’s Hospital, Mansoura University, Mansoura, 35516, Egypt
* Address correspondence to: Attalla F. El-Kott,
BIOCELL 2021, 45(5), 1337-1353. https://doi.org/10.32604/biocell.2021.015464
Received 20 December 2020; Accepted 16 March 2021; Issue published 12 July 2021
Abstract
This study examined if the anti-tumorigenesis effect of Exendin-4 in HT29 and HCT116 colorectal
cancer (CRC) involves modulation of SIRT1 and Akt/GSR3K/β-catenin/NF-κB axis. HT29 and HCT116 cells were
treated either with increasing levels of Exendin-4 (0.0-200 µM) or with Exendin-4 (at its IC
50) in the presence or
absence of EX-527 (10 µM/a selective SIRT1 inhibitor) or Exendin-4 (9-39) amide (E (9-39) A) (1 µM/an Exendin-4
antagonist). In a dose-dependent manner, Exendin-4 inhibited cell survival, but enhanced levels of lactate
dehydrogenase (LDH) and single-stranded DNA (ssDNA) in both HT29 and HCT116. In both cell lines and at it has
an IC
50 (45 µM for HT29 and 35 µM for HCT1165), Exendin-4 also significantly reduced cell survival, migration, and
invasion of both cell types, with no effect on the expression GLP-1 receptors (GLPRs) nor of the activity of Akt. At
these doses, Exendin-4 also increased the expression of SIRT1 but reduced the acetylation of NF-κB and the
expression of Bax and cleaved caspase-3 and in both cell lines. Concomitantly, protein levels of p-GS3Kβ (Ser
9
), total
and acetylated β-catenin, and Anix2 were significantly decreased, but levels of p-GS3Kβ (Ser
9
) and p-β-catenin
(Ser
33/37/Thr
41) were significantly increased in both HT29 and HCT116-exendin-4 treated cells. All the effects exerted
by Exendin-4 were completely prevented by Ex527 or E (9-39) A. In conclusion, Exendin-4 suppresses the
tumorigenesis of HT29 and HCT116 CRC cell activation of GS3Kβ-induced inhibition of β-catenin and NF-κβ in a
SIRT1-dependent mechanism.
Keywords
Cite This Article
EL-KOTT, A. F., EL-KENAWY, A. E., ELBEALY, E. R., ALSHEHRI, A. S., KHALIFA, H. S. et al. (2021). Exendin-4 inhibits the survival and invasiveness of two colorectal cancer cell lines via suppressing GS3Kβ/β-catenin/NF-κB axis through activating SIRT1.
BIOCELL, 45(5), 1337–1353. https://doi.org/10.32604/biocell.2021.015464