Background: The biological mechanisms underlying early-and advanced-stage epithelial ovarian cancers (EOCs) are still poorly understood. This study explored kinase-driven metabolic signalling in early and advanced EOCs, and its role in tumour progression and response to carboplatin-paclitaxel treatment. Methods: Tumour epithelia were isolated from two independent sets of primary EOC (n-72 and 30 for the discovery and the validation sets, respectively) via laser capture microdissection. Reverse phase protein microarrays were used to broadly profile the kinase-driven metabolic signalling of EOC with particular emphasis on the LBK1-AMPK and AKT-mTOR axes. Signalling activation was compared between early and advanced lesions, and carboplatin-paclitaxel-sensitive and -resistant tumours. Results: Advanced EOCs were characterised by a heterogeneous kinase-driven metabolic signature and decreased phosphorylation of the AMPK-AKT-mTOR axis compared to early EOC (P<0.05 for AMPK alpha T172, AMPK alpha 1 S485, AMPK beta 1 S108, AKT S473 and T308, mTOR S2448, p70S6 S371, 4EBP1 S65, GSK-3 alpha/beta S21/9, FOXO1 T24/FOXO3 T32, and FOXO1 S256). Advanced tumours with low relative activation of the metabolic signature and increased FOXO1 T24/FOXO3 T32 phosphorylation (P=0.041) were associated with carboplatin-paclitaxel resistance. Conclusions: If validated in a larger cohort of patients, the decreased AMPK-AKT-mTOR activation and phosphorylation of FOXO1 T24/FOXO3 T32 may help identify carboplatin-paclitaxel-resistant EOC patients.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/625488 |
| Date | 29 June 2017 |
| Creators | Sereni, Maria Isabella, Baldelli, Elisa, Gambara, Guido, Ravaggi, Antonella, Hodge, K Alex, Alberts, David S, Guillen-Rodriguez, Jose M, Dong, Ting, Memo, Maurizio, Odicino, Franco, Angioli, Roberto, Liotta, Lance A, Pecorelli, Sergio L, Petricoin, Emanuel F, Pierobon, Mariaelena |
| Contributors | Univ Arizona, Ctr Canc |
| Publisher | NATURE PUBLISHING GROUP |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | Article |
| Rights | Copyright © 2017, Rights Managed by Nature Publishing Group |
| Relation | http://www.nature.com/doifinder/10.1038/bjc.2017.195 |
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