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 ELBEALY 3 ;FAHMY ELSAID 1,4 ;HAITHAM EL-MEKKAWY 1 ;ABD-EL-KARIM ABD-LATEIF 5 ; ABDULALI TAWEEL 6 ;HEBA KHALIFA 2 ;AHMAD KANDEEL 5 ;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 Key words: Pterostilbene, Ovarian cancer, Lipogenesis, Apoptosis, AMPK 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 (IC 50 = 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 tumor- suppressive 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. Introduction Ovarian cancer (OC) is a common gynecological malignancy that usually affects postmenopausal women (Wang et al ., 2005). Currently, the available treatment of OC involves surgical resection, followed by adjuvant systemic chemotherapy that consists of a combination of platinum and/or taxane-based chemotherapy (Elias et al., 2018). However, the mortality rates remain very high among patients with OC, where the overall 5-year survival rate is less than 40% (Webb and Jordan, 2017). This has been attributed to a lack of symptoms during the initial phases (poor detection), *Address correspondence to: Mashael Mohammed Bin-Meferij, mmbinmufayrij@pnu.edu.sa Received: 02 July 2020; Accepted: 23 September 2020 BIOCELL ech T Press Science 2021 45(1): 89-101 Doi: 10.32604/biocell.2021.012516 www.techscience.com/journal/biocell This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.