Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy

<b>Background</b>: Ovarian cancer progression and invasiveness are promoted by a range of soluble factors released by cancer cells and stromal cells within the tumor microenvironment. Our previous studies demonstrated that resveratrol (RV), a nutraceutical and caloric restriction mimetic...

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Autores principales:	Alessandra Ferraresi, Andrea Esposito, Carlo Girone, Letizia Vallino, Amreen Salwa, Ian Ghezzi, Suyanee Thongchot, Chiara Vidoni, Danny N. Dhanasekaran, Ciro Isidoro
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	autophagy tumor microenvironment cell migration epithelial to mesenchymal transition BMI-1 3D spheroids Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/ba1e3c4e2a3d45cd91d8feac57234f43
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spelling	oai:doaj.org-article:ba1e3c4e2a3d45cd91d8feac57234f432021-11-25T17:12:57ZResveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy10.3390/cells101132132073-4409https://doaj.org/article/ba1e3c4e2a3d45cd91d8feac57234f432021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3213https://doaj.org/toc/2073-4409<b>Background</b>: Ovarian cancer progression and invasiveness are promoted by a range of soluble factors released by cancer cells and stromal cells within the tumor microenvironment. Our previous studies demonstrated that resveratrol (RV), a nutraceutical and caloric restriction mimetic with tumor-suppressive properties, counteracts cancer cell motility induced by stromal IL-6 by upregulating autophagy. Lysophosphatidic acid (LPA), a bioactive phospholipid that shows elevated levels in the tumor microenvironment and the ascites of ovarian cancers, stimulates the growth and tissue invasion of cancer cells. Whether LPA elicits these effects by inhibiting autophagy and through which pathway and whether RV can counteract the same remain obscure. <b>Aims</b>: To investigate the molecular pathways involved in LPA-induced ovarian cancer malignancy, particularly focusing on the role of autophagy, and the ability of RV to counteract LPA activity. <b>Results</b>: LPA stimulated while RV inhibited ovarian cancer cell migration. Transcriptomic and bioinformatic analyses showed an opposite regulation by LPA and RV of genes linked to epithelial-to-mesenchymal transition (EMT) and autophagy with involvement of the PI3K-AKT, JAK-STAT and Hedgehog (Hh) pathways. LPA upregulated the Hh and EMT members GLI1, BMI-1, SNAIL-1 and TWIST1 and inhibited autophagy, while RV did the opposite. Similar to the inhibitors of the Hh pathway, RV inhibited LPA-induced cancer cell migration and 3D growth of ovarian cancer cells. <i>BMI-1</i> silencing prevented LPA-induced EMT, restored autophagy and hampered cell migration, resembling the effects of RV. TCGA data analyses indicated that patients with low expression of Hh/EMT-related genes together with active autophagy flux tended to have a better prognosis and this correlates with a more effective response to platinum therapy. In <i>in vitro</i> 3D spheroids, LPA upregulated BMI-1, downregulated autophagy and inhibited platinum toxicity while RV and Hh inhibitors restored autophagy and favored BAX-mediated cell death in response to platinum. <b>Conclusions</b>: By inhibiting the Hh pathway and restoration of autophagy, RV counteracts LPA-induced malignancy, supporting its inclusion in the therapy of ovarian cancer for limiting metastasis and chemoresistance.Alessandra FerraresiAndrea EspositoCarlo GironeLetizia VallinoAmreen SalwaIan GhezziSuyanee ThongchotChiara VidoniDanny N. DhanasekaranCiro IsidoroMDPI AGarticleautophagytumor microenvironmentcell migrationepithelial to mesenchymal transitionBMI-13D spheroidsBiology (General)QH301-705.5ENCells, Vol 10, Iss 3213, p 3213 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	autophagy tumor microenvironment cell migration epithelial to mesenchymal transition BMI-1 3D spheroids Biology (General) QH301-705.5
spellingShingle	autophagy tumor microenvironment cell migration epithelial to mesenchymal transition BMI-1 3D spheroids Biology (General) QH301-705.5 Alessandra Ferraresi Andrea Esposito Carlo Girone Letizia Vallino Amreen Salwa Ian Ghezzi Suyanee Thongchot Chiara Vidoni Danny N. Dhanasekaran Ciro Isidoro Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy
description	<b>Background</b>: Ovarian cancer progression and invasiveness are promoted by a range of soluble factors released by cancer cells and stromal cells within the tumor microenvironment. Our previous studies demonstrated that resveratrol (RV), a nutraceutical and caloric restriction mimetic with tumor-suppressive properties, counteracts cancer cell motility induced by stromal IL-6 by upregulating autophagy. Lysophosphatidic acid (LPA), a bioactive phospholipid that shows elevated levels in the tumor microenvironment and the ascites of ovarian cancers, stimulates the growth and tissue invasion of cancer cells. Whether LPA elicits these effects by inhibiting autophagy and through which pathway and whether RV can counteract the same remain obscure. <b>Aims</b>: To investigate the molecular pathways involved in LPA-induced ovarian cancer malignancy, particularly focusing on the role of autophagy, and the ability of RV to counteract LPA activity. <b>Results</b>: LPA stimulated while RV inhibited ovarian cancer cell migration. Transcriptomic and bioinformatic analyses showed an opposite regulation by LPA and RV of genes linked to epithelial-to-mesenchymal transition (EMT) and autophagy with involvement of the PI3K-AKT, JAK-STAT and Hedgehog (Hh) pathways. LPA upregulated the Hh and EMT members GLI1, BMI-1, SNAIL-1 and TWIST1 and inhibited autophagy, while RV did the opposite. Similar to the inhibitors of the Hh pathway, RV inhibited LPA-induced cancer cell migration and 3D growth of ovarian cancer cells. <i>BMI-1</i> silencing prevented LPA-induced EMT, restored autophagy and hampered cell migration, resembling the effects of RV. TCGA data analyses indicated that patients with low expression of Hh/EMT-related genes together with active autophagy flux tended to have a better prognosis and this correlates with a more effective response to platinum therapy. In <i>in vitro</i> 3D spheroids, LPA upregulated BMI-1, downregulated autophagy and inhibited platinum toxicity while RV and Hh inhibitors restored autophagy and favored BAX-mediated cell death in response to platinum. <b>Conclusions</b>: By inhibiting the Hh pathway and restoration of autophagy, RV counteracts LPA-induced malignancy, supporting its inclusion in the therapy of ovarian cancer for limiting metastasis and chemoresistance.
format	article
author	Alessandra Ferraresi Andrea Esposito Carlo Girone Letizia Vallino Amreen Salwa Ian Ghezzi Suyanee Thongchot Chiara Vidoni Danny N. Dhanasekaran Ciro Isidoro
author_facet	Alessandra Ferraresi Andrea Esposito Carlo Girone Letizia Vallino Amreen Salwa Ian Ghezzi Suyanee Thongchot Chiara Vidoni Danny N. Dhanasekaran Ciro Isidoro
author_sort	Alessandra Ferraresi
title	Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy
title_short	Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy
title_full	Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy
title_fullStr	Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy
title_full_unstemmed	Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy
title_sort	resveratrol contrasts lpa-induced ovarian cancer cell migration and platinum resistance by rescuing hedgehog-mediated autophagy
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/ba1e3c4e2a3d45cd91d8feac57234f43
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Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy

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