Effect of combined inhibition of p110 alpha PI3K isoform and STAT3 pathway in ovarian cancer platinum-based resistance
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Augustin Le Naour1, Renaud Mevel1, Benoit Thibault1, Elise Courtais1, Elodie Chantalat2, Jean Pierre Delord1,3, Bettina Couderc1,4, Julie Guillermet-Guibert1,5 and Alejandra Martinez1,2
1Centre de Recherches en Cancérologie de Toulouse (CRCT), UMR 1037 INSERM, University Toulouse III, Toulouse, France
2Department Surgical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France
3Department Medical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France
4Department Biology, Institut Claudius Regaud, Institut Universitaire du Cancer, Toulouse, France
5Laboratoire d'excellence LABEX TouCAN, Toulouse, France
Alejandra Martinez, email: [email protected]
Keywords: ovarian cancer; IL-6; chemoresistance; PI3KCA; ascites
Received: November 27, 2017 Accepted: April 07, 2018 Published: June 05, 2018
Background: Ovarian cancer is associated with poor prognostic outcome due to late diagnosis and to intrinsic and acquired resistance to platinum-based chemotherapy in a large number of patients. This chemoresistance is acquired through the peritoneal and ascites microenvironment by several released factors, such as IL-6,. Preclinical studies have implicated the activation of PI3K pathway in chemoresistance, showing it to extend tumor cell survival and modulate multidrug resistance. We aimed to evaluate the implication of the p110 alpha PI3K subunit in ovarian cancer chemoresistance acquisition, and to evaluate whether the STAT3 pathway can mediate resistance to PI3K inhibitors through secretion of IL6.
Results: Human ovarian adenocarcinoma IGROV-1 and JHOC-5 cells cultured in ascites showed an increase in carboplatinum-based resistance. Level of chemoresistance was associated to IL6 concentration in ascites. Activation of PI3K/Akt, STAT and MAPK pathways was observed after IGROV-1 incubation with ascites and treatment with carboplatin. Neither IGROV-1 nor JHOC-5 cells exposed to ascites treated with additional IL-6 directed antibody showed any reversion of the chemoresistance.
Conclusion: IL6-related resistance was not abolished by the selective inhibition of PI3K alpha subunit coupled with the anti-IL6-receptor antibody tocilizumab. This dual inhibition requires further exploration in other ovarian cancer models such as clear cell carcinoma.
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