Aclidinium inhibits proliferation and metastasis of ovarian cancer SKOV3 cells via downregulating PI3K/AKT/mTOR signaling pathway

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Abstract

Aclidinium, a muscarinic antagonist, is generally used to treat the respiratory system diseases whereas it is not clear whether aclidinium has therapeutic effect in ovarian cancer (OC). The aim of this study was to investigate the impact of aclidinium on OC and its potential mechanism. CCK-8 was employed to test the potential effect of aclidinium on SKOV3 cell proliferation. Transwell migration and invasion assay was performed to assess the influence of aclidinium on SKOV3 cell metastasis and invasion. Furthermore, flow cytometry apoptotic analysis was used to evaluate the effect of aclidinium on cell apoptosis. Finally, western blotting was applied to determine the changes of key proteins in apoptosis and PI3K/AKT/mTOR signaling pathway induced by aclidinium. The study showed that aclidinium had antiproliferative activity on SKOV3 cells. Simultaneously, aclidinium could significantly inhibit the number of migrated and invaded SKOV3 cells and markedly increased the SKOV3 cell apoptosis rate. Mechanistically, the expression of PI3K/AKT/mTOR signaling pathway related proteins were significantly inhibited in aclidinium treated SKOV3 cells. Our findings proposed a clue for further OC studies in preclinical and clinical treatment and aclidinium may be useful for the treatment of OC in the future.

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PIK3CA is implicated as an oncogene in ovarian cancer.

L Shayesteh, Y. Lu, W L Kuo … (1999)

Ovarian cancer is the leading cause of death from gynecological malignancy and the fourth leading cause of cancer death among American women, yet little is known about its molecular aetiology. Studies using comparative genomic hybridization (CGH) have revealed several regions of recurrent, abnormal, DNA sequence copy number that may encode genes involved in the genesis or progression of the disease. One region at 3q26 found to be increased in copy number in approximately 40% of ovarian and others cancers contains PIK3CA, which encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3-kinase). The association between PIK3CA copy number and PI3-kinase activity makes PIK3CA a candidate oncogene because a broad range of cancer-related functions have been associated with PI3-kinase mediated signalling. These include proliferation, glucose transport and catabolism, cell adhesion, apoptosis, RAS signalling and oncogenic transformation. In addition, downstream effectors of PI3-kinase, AKT1 and AKT2, have been found to be amplified or activated in human tumours, including ovarian cancer. We show here that PIK3CA is frequently increased in copy number in ovarian cancers, that the increased copy number is associated with increased PIK3CA transcription, p110alpha protein expression and PI3-kinase activity and that treatment with the PI3-kinase inhibitor LY294002 decreases proliferation and increases apoptosis. Our observations suggest PIK3CA is an oncogene that has an important role in ovarian cancer.

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The Importance of the PI3K/AKT/MTOR Pathway in the Progression of Ovarian Cancer

Zachary Dobbin, Charles N. Landen (2013)

Ovarian cancer is the fifth most common cause of death due to cancer in women despite being the tenth in incidence. Unfortunately, the five-year survival rate is only 45%, which has not improved much in the past 30 years. Even though the majority of women have successful initial therapy, the low rate of survival is due to the eventual recurrence and succumbing to their disease. With the recent release of the Cancer Genome Atlas for ovarian cancer, it was shown that the PI3K/AKT/mTOR pathway was one of the most frequently mutated or altered pathways in patients’ tumors. Researching how the PI3K/AKT/mTOR pathway affects the progression and tumorigensis of ovarian cancer will hopefully lead to new therapies that will increase survival for women. This review focuses on recent research on the PI3K/AKT/mTOR pathway and its role in the progression and tumorigensis of ovarian cancer.

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The PI3K/Akt/mTOR signaling pathway mediates insulin-like growth factor 1-induced E-cadherin down-regulation and cell proliferation in ovarian cancer cells.

Man-Tat Lau, Peter Leung (2012)

Insulin-like growth factor 1 (IGF1) is produced by ovarian cancer cells and it has been suggested that it plays an important role in tumor progression. In this study, we report that IGF1 treatment down-regulated E-cadherin by up-regulating E-cadherin transcriptional repressors, Snail and Slug, in human ovarian cancer cells. The pharmacological inhibition of phosphatidylinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) suggests that PI3K/Akt/mTOR signaling is required for IGF1-induced E-cadherin down-regulation. Moreover, IGF1 up-regulated Snail and Slug expression via the PI3K/Akt/mTOR signaling pathway. Finally, IGF1-induced cell proliferation was abolished by inhibiting PI3K/Akt/mTOR signaling. This study demonstrates a novel mechanism in which IGF1 down-regulates E-cadherin expression through the activation of PI3K/Akt/mTOR signaling and the up-regulation of Snail and Slug in human ovarian cancer cells. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Oncol Lett

Journal ID (iso-abbrev): Oncol Lett

Journal ID (publisher-id): OL

Title: Oncology Letters

Publisher: D.A. Spandidos

ISSN (Print): 1792-1074

ISSN (Electronic): 1792-1082

Publication date (Print): November 2018

Publication date (Electronic): 19 September 2018

Publication date PMC-release: 19 September 2018

Volume: 16

Issue: 5

Pages: 6417-6422

Affiliations

[1 ]Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China

[2 ]Gynecology Department Five of The Harbin Red Cross Center Hospital, Harbin, Heilongjiang 150076, P.R. China

[3 ]Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570203, P.R. China

Author notes

Correspondence to: Dr Yuan Zhang, Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Hainan Medical University, 10 Haifu Road, Haikou, Hainan 570203, P.R. China, E-mail: 13016231168@ 123456163.com

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Publisher ID: OL-0-0-9460

DOI: 10.3892/ol.2018.9460

PMC ID: 6202542

PubMed ID: 30405778

SO-VID: 0c79c5a4-e0c7-4c0b-a11c-f3d86971d9e4

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This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Aclidinium inhibits proliferation and metastasis of ovarian cancer SKOV3 cells via downregulating PI3K/AKT/mTOR signaling pathway

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Karger: Oncology

Most cited references 25

PIK3CA is implicated as an oncogene in ovarian cancer.

The Importance of the PI3K/AKT/MTOR Pathway in the Progression of Ovarian Cancer

The PI3K/Akt/mTOR signaling pathway mediates insulin-like growth factor 1-induced E-cadherin down-regulation and cell proliferation in ovarian cancer cells.

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