Salidroside induces cell apoptosis and inhibits the invasiveness of HT29 colorectal cells by regulating protein kinase R, NF-κB and STAT3

Article type: Research Article

Authors: El-kott, Attalla F.^{a; b; *} | ElBealy, Eman R.^c | Alshehri, Ali S.^a | El-Kenawy, Ayman E.^d | Khalifa, Heba S.^b | AlRamlawy, Amira M.^e

Affiliations: [a] Biology Department, College of Science, King Khalid University, Abha, Saudi Arabia | [b] Zoology Department, College of Science, Damanhour University, Damanhour, Egypt | [c] Biology Department, College of Science for Girls, King Khalid University, Abha, Saudi Arabia | [d] Pathology Department, College of Medicine, Taif University, Taif, Saudi Arabia | [e] Mansoura Research Centre for Cord Stem Cell (MARC-CSC), Stem Cells Bank, Children’s Hospital, Mansoura University, Mansoura, Egypt

Correspondence: [*] Corresponding author: Attalla F. El-kott, Biology Department, College of Science, King Khalid University, Abha, Saudi Arabia. %****␣cbm-31-cbm203257_temp.tex␣Line␣25␣**** E-mail: [email protected];[email protected].

Abstract: BACKGROUND: Protein kinase R (PKR) can suppress various types of solid tumors by inducing cellular oxidative stress and apoptosis. Likewise, Slaidorside, a plant flavonoid, was shown to have anti-tumorigenesis in many solid tumors. OBJECTIVE: This study evaluated anti-tumorigenesis of Salidroside in HT29 colorectal cancer and investigated if the underlying mechanism involves activation of PKR. METHODS: Control or PKR deficient cells were cultured in DMEM media treated with 100 μM Salidroside and cell survival, apoptosis, and other biochemical-related markers were evaluated. RESULTS: Salidroside significantly reduced cell survival and proliferation and increased the release of lactate dehydrogenase (LDH) and levels of single-stranded DNA (ssDNA). It also increased the protein levels of caspases 3 and 8. Concomitantly, Salidroside increased the protein level and activity of PKR and increased the expression of its downstream targets, p-eIF2α (Ser51), p53 MAPK, and p53. On the contrary, it inhibited the nuclear activation of STAT-3 and NF-κB p65. In PKR deficient cells, the partial effects of Salidroside on cell survival, proliferation, and apoptotic markers were observed coincided with no effects on the expression of eIF-2α, and JNK, p53, p38 MAPK, and caspase 8 but with a significant decrease in the nuclear activities of STAT3 and NF-κB. CONCLUSION: Salidroside suppresses the tumorigenesis of HT29 CRC by increasing activation of eIF-2α and JNK and upregulation of p53, p38 MAPK, and caspase-8 through upregulating and activation of PKR. However, the tumor suppressor effect of Salidroside requires also inhibition of STAT3 and NF-κB in a PKR-independent mechanism.

Keywords: Salidroside, colorectal, HT29, protein kinase R, STAT3, eIF-2α, NF-κB

DOI: 10.3233/CBM-203257

Journal: Cancer Biomarkers, vol. 31, no. 1, pp. 13-25, 2021