title: mPGES-1 in prostate cancer controls stemness and amplifies epidermal growth factor receptor-driven oncogenicity.
abstract: There is evidence that an inflammatory microenvironment is associated with the development and progression of prostate cancer (PCa), although the determinants of intrinsic inflammation in PCa cells are not completely understood. Here we investigated whether expression of intrinsic microsomal PGE synthase-1 (mPGES-1) enhanced aggressiveness of PCa cells and might be critical for epidermal growth factor receptor (EGFR)-mediated tumour progression. In PCa, overexpression of EGFR promotes metastatic invasion and correlates with a high Gleason score, while prostaglandin E2 (PGE2) has been reported to modulate oncogenic EGFR-driven oncogenicity. Immunohistochemical studies revealed that mPGES-1 in human prostate tissues is correlated with EGFR expression in advanced tumours. In DU145 and PC-3 cell lines expressing mPGES-1 (mPGES-1(SC) cells), we demonstrate that silencing or 'knock down' of mPGES-1 (mPGES-1(KD)) or pharmacological inhibition by MF63 strongly attenuates overall oncogenic drive. Indeed, mPGES-1(SC) cells express stem-cell-like features (high CD44, β1-integrin, Nanog and Oct4 and low CD24 and α6-integrin) as well as mesenchymal transition markers (high vimentin, high fibronectin, low E-cadherin). They also show increased capacity to survive irrespective of anchorage condition, and overexpress EGFR compared to mPGES-1(KD) cells. mPGES-1 expression correlates with increased in vivo tumour growth and metastasis. Although EGFR inhibition reduces mPGES-1(SC) and mPGES-1(KD) cell xenograft tumour growth, we show that mPGES-1/PGE2 signalling sensitizes tumour cells to EGFR inhibitors. We propose mPGES-1 as a possible new marker of tumour aggressiveness in PCa.
authors.affiliation: Department of Life SciencesUniversity of Siena, Via Aldo Moro 2, 53100 Siena, ItalyDepartment of Surgery and Translational MedicineUniversity of Florence, Largo Brambilla 3, 50134 Firenze, ItalyDepartment of Clinical and Experimental MedicineUniversity of Florence, Viale Pieraccini 18, 50139 Firenze, ItalyDepartment of Medical Biochemistry and BiophysicsKarolinska Institutet, SE-171 77 Stockholm, SwedenIstituto Toscano Tumori (ITT)Firenze, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Finetti
authors.affiliation: Department of Life SciencesUniversity of Siena, Via Aldo Moro 2, 53100 Siena, ItalyDepartment of Surgery and Translational MedicineUniversity of Florence, Largo Brambilla 3, 50134 Firenze, ItalyDepartment of Clinical and Experimental MedicineUniversity of Florence, Viale Pieraccini 18, 50139 Firenze, ItalyDepartment of Medical Biochemistry and BiophysicsKarolinska Institutet, SE-171 77 Stockholm, SwedenIstituto Toscano Tumori (ITT)Firenze, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Terzuoli
authors.affiliation: Department of Life SciencesUniversity of Siena, Via Aldo Moro 2, 53100 Siena, ItalyDepartment of Surgery and Translational MedicineUniversity of Florence, Largo Brambilla 3, 50134 Firenze, ItalyDepartment of Clinical and Experimental MedicineUniversity of Florence, Viale Pieraccini 18, 50139 Firenze, ItalyDepartment of Medical Biochemistry and BiophysicsKarolinska Institutet, SE-171 77 Stockholm, SwedenIstituto Toscano Tumori (ITT)Firenze, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giachetti
authors.affiliation: Department of Life SciencesUniversity of Siena, Via Aldo Moro 2, 53100 Siena, ItalyDepartment of Surgery and Translational MedicineUniversity of Florence, Largo Brambilla 3, 50134 Firenze, ItalyDepartment of Clinical and Experimental MedicineUniversity of Florence, Viale Pieraccini 18, 50139 Firenze, ItalyDepartment of Medical Biochemistry and BiophysicsKarolinska Institutet, SE-171 77 Stockholm, SwedenIstituto Toscano Tumori (ITT)Firenze, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Santi
authors.affiliation: Department of Life SciencesUniversity of Siena, Via Aldo Moro 2, 53100 Siena, ItalyDepartment of Surgery and Translational MedicineUniversity of Florence, Largo Brambilla 3, 50134 Firenze, ItalyDepartment of Clinical and Experimental MedicineUniversity of Florence, Viale Pieraccini 18, 50139 Firenze, ItalyDepartment of Medical Biochemistry and BiophysicsKarolinska Institutet, SE-171 77 Stockholm, SwedenIstituto Toscano Tumori (ITT)Firenze, Italy.
authors.forename: Donata
authors.initials: D
authors.lastname: Villari
authors.affiliation: Department of Life SciencesUniversity of Siena, Via Aldo Moro 2, 53100 Siena, ItalyDepartment of Surgery and Translational MedicineUniversity of Florence, Largo Brambilla 3, 50134 Firenze, ItalyDepartment of Clinical and Experimental MedicineUniversity of Florence, Viale Pieraccini 18, 50139 Firenze, ItalyDepartment of Medical Biochemistry and BiophysicsKarolinska Institutet, SE-171 77 Stockholm, SwedenIstituto Toscano Tumori (ITT)Firenze, Italy.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hanaka
authors.affiliation: Department of Life SciencesUniversity of Siena, Via Aldo Moro 2, 53100 Siena, ItalyDepartment of Surgery and Translational MedicineUniversity of Florence, Largo Brambilla 3, 50134 Firenze, ItalyDepartment of Clinical and Experimental MedicineUniversity of Florence, Viale Pieraccini 18, 50139 Firenze, ItalyDepartment of Medical Biochemistry and BiophysicsKarolinska Institutet, SE-171 77 Stockholm, SwedenIstituto Toscano Tumori (ITT)Firenze, Italy.
authors.forename: Olof
authors.initials: O
authors.lastname: Radmark
authors.affiliation: Department of Life SciencesUniversity of Siena, Via Aldo Moro 2, 53100 Siena, ItalyDepartment of Surgery and Translational MedicineUniversity of Florence, Largo Brambilla 3, 50134 Firenze, ItalyDepartment of Clinical and Experimental MedicineUniversity of Florence, Viale Pieraccini 18, 50139 Firenze, ItalyDepartment of Medical Biochemistry and BiophysicsKarolinska Institutet, SE-171 77 Stockholm, SwedenIstituto Toscano Tumori (ITT)Firenze, Italy Department of Life SciencesUniversity of Siena, Via Aldo Moro 2, 53100 Siena, ItalyDepartment of Surgery and Translational MedicineUniversity of Florence, Largo Brambilla 3, 50134 Firenze, ItalyDepartment of Clinical and Experimental MedicineUniversity of Florence, Viale Pieraccini 18, 50139 Firenze, ItalyDepartment of Medical Biochemistry and BiophysicsKarolinska Institutet, SE-171 77 Stockholm, SwedenIstituto Toscano Tumori (ITT)Firenze, Italy sandra.donnini@unisi.it marina.ziche@unisi.it.
authors.forename: Marina
authors.initials: M
authors.lastname: Ziche
authors.affiliation: Department of Life SciencesUniversity of Siena, Via Aldo Moro 2, 53100 Siena, ItalyDepartment of Surgery and Translational MedicineUniversity of Florence, Largo Brambilla 3, 50134 Firenze, ItalyDepartment of Clinical and Experimental MedicineUniversity of Florence, Viale Pieraccini 18, 50139 Firenze, ItalyDepartment of Medical Biochemistry and BiophysicsKarolinska Institutet, SE-171 77 Stockholm, SwedenIstituto Toscano Tumori (ITT)Firenze, Italy Department of Life SciencesUniversity of Siena, Via Aldo Moro 2, 53100 Siena, ItalyDepartment of Surgery and Translational MedicineUniversity of Florence, Largo Brambilla 3, 50134 Firenze, ItalyDepartment of Clinical and Experimental MedicineUniversity of Florence, Viale Pieraccini 18, 50139 Firenze, ItalyDepartment of Medical Biochemistry and BiophysicsKarolinska Institutet, SE-171 77 Stockholm, SwedenIstituto Toscano Tumori (ITT)Firenze, Italy sandra.donnini@unisi.it marina.ziche@unisi.it.
authors.forename: Sandra
authors.initials: S
authors.lastname: Donnini
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D015232:Dinoprostone; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D020868:Gene Silencing; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D039503:Integrin alpha6 / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D008819:Mice, Nude; D000071876:Prostaglandin-E Synthases; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D039503:Integrin alpha6; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone
keywords: EGFR; EMT; mPGES-1; prostate cancer; stemness