Open Access

ARTICLE

Pterostilbene induces cell apoptosis and inhibits lipogenesis in SKOV3 ovarian cancer cells by activation of AMPK-induced inhibition of Akt/mTOR signaling cascade

ATTALLA EL-KOTT^1,2, EMAN ELBEALY³, FAHMY ELSAID^1,4, HAITHAM EL-MEKKAWY¹, ABD-EL-KARIM ABD-LATEIF⁵, ABDULALI TAWEEL⁶, HEBA KHALIFA², AHMAD KANDEEL⁵, KAREEM MORSY^1,7, ESSAM IBRAHIM^1,8,9, MASHAEL MOHAMMED BIN-MEFERIJ^10,*

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 Biology Department, College of Science for Girls, King Khalid University, Abha, 61413, Saudi Arabia
4 Zoology Department, College of Science, Mansoura University, Mansoura, 35511, Egypt
5 Zoology Department, College of Science, Fayoum University, Fayoum, 63511, Egypt
6 Zoology Department, Faculty of Science, Al-Zawia University, Al-Zawia, Libya
7 Biology Department, Faculty of Science, Cairo University, Cairo, 12611, Egypt
8 Research Center for Advanced Materials Science (RCAMS), King Khalid University, Abha, 61413, Saudi Arabia
9 Blood Products Quality Control and Research Department, National Organization for Research and Control of Biologicals, Cairo, 12611, Egypt
10 Biology Department, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia

* Address correspondence to: Mashael Mohammed Bin-Meferij,

BIOCELL 2021, 45(1), 89-101. https://doi.org/10.32604/biocell.2021.012516

Received 02 July 2020; Accepted 23 September 2020; Issue published 26 January 2021

Abstract

This study investigates if the anti-tumor effect of Pterostilbene in the SKOV3 ovarian cancer (OC) cell line involves inhibition of cell metabolism and tested in this effect involves modulating AMPK and Akt-induced regulation of mTORC1. Initially, SKOV3 cells were cultured in the humidified conditions in DMEM media for 24 h with or without increasing concentration of Pterostilbene. Then, the cells were incubated with Pterostilbene (IC₅₀ = 50 µM) under similar conditions with or without pre-incubation with Dorsomorphin, an AMPK inhibitor. In a dose-dependent manner, Pterostilbene inhibited SKOV3 cell survival and increased their lysate levels of lactate dehydrogenase (LDH) and single-stranded DNA (ssDNA). When SKOV3 cells were treated with 50 µM Pterostilbene, Pterostilbene significantly suppressed cell migration and invasion, reduced lysate levels of lactic acid and the optical density of Oil Red O staining, and increased lysate glucose levels. It also increased levels of malondialdehyde (MDA), reactive oxygen species (ROS), and induced intrinsic cell apoptosis by upregulating protein levels of Bax and cleaved caspase-3 and reducing protein levels of Bcl-2. Besides, Pterostilbene reduced mRNA levels of sterol regulatory element-binding protein 1 (SREBP-1), fatty acid synthase (FAS), acetyl CoA carboxylase-1 (ACC-1), and AMP-activated protein kinase (AMPK). Furthermore, Pterostilbene increased the protein levels of p-AMPK, p-p53, p-raptor, p-TSC-2, but significantly decreased protein levels of p-Akt, p-TSC-2, p-mTOR, p-S6K1, and p-4E-BP. Treatment with Dorsomorphin (CC) abolished all the anti-tumorigenesis effects afforded by Pterostilbene and prevented Pterostilbene-induced phosphorylation of Akt, p53, and mTOR. In conclusion, the tumorsuppressive effect of Pterostilbene in SKOV3 cells involves the induction of ROS and inhibition of dysregulation cell metabolism mainly due to AMPK-induced Akt-dependent or independent suppression of mTOR.

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