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 E 2 (PGE 2 ) 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/PGE 2 signalling sensitizes tumour cells to EGFR inhibitors. We propose mPGES-1 as a possible new marker of tumour aggressiveness in PCa

MPGES-1 in prostate cancer controls stemness and amplifies epidermal growth factor receptor-driven oncogenicity / Finetti F.; Terzuoli E.; Giachetti A.; Santi R.; Villari D.; Hanaka H.; Radmark O.; Ziche M.; Donnini S.. - In: ENDOCRINE-RELATED CANCER. - ISSN 1351-0088. - ELETTRONICO. - 22:(2015), pp. 665-678. [10.1530/ERC-15-0277]

MPGES-1 in prostate cancer controls stemness and amplifies epidermal growth factor receptor-driven oncogenicity

Santi R.;Villari D.;Ziche M.;
2015

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 E 2 (PGE 2 ) 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/PGE 2 signalling sensitizes tumour cells to EGFR inhibitors. We propose mPGES-1 as a possible new marker of tumour aggressiveness in PCa
2015
22
665
678
Goal 4: Quality education
Finetti F.; Terzuoli E.; Giachetti A.; Santi R.; Villari D.; Hanaka H.; Radmark O.; Ziche M.; Donnini S.
File in questo prodotto:
File Dimensione Formato  
mPGES-1 in prostate cancer Finetti 2015.pdf

accesso aperto

Tipologia: Pdf editoriale (Version of record)
Licenza: Open Access
Dimensione 580.69 kB
Formato Adobe PDF
580.69 kB Adobe PDF

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1179001
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 41
  • ???jsp.display-item.citation.isi??? 38
social impact