Colorectal cancer (CRC) has an elevated incidence worldwide and represents one of the most aggressive human tumours. Many experimental data provide the evidence of a strong association between cyclooxygenase-2 (COX-2) enzyme overexpression and colon tumorigenesis. Furthermore, it has been demonstrated that the chronic use of non-steroidal anti-inflammatory drugs (NSAIDs, a class of COX-2 inhibitors), partially protects patients from CRC development and progression. Unfortunately, NSAIDs have been shown to induce severe side effects in chronically treated patients and, therefore, new strategies for selective COX-2 blockade are needed. In this paper we present an innovative COX-2 silencing approach mediated by RNA Interference (RNAi) which is a mechanism we have already described as a powerful tool to knockdown COX-2 protein in CRC cells. In particular, we developed an improved method to gain a highly selective COX-2 silencing in CRC cells by a tumour-dependent expression of anti-COX-2 short hairpin RNA (shCOX-2). Moreover, we efficiently delivered shCOX-2 expressing vectors in CRC cells, in vitro and ex vivo, by using engineered Escherichia coli strains, capable of infecting and invading human tumour cells (InvColi). Combining the highly selective shCOX-2 expression and the delivery of COX-2 silencers mediated by InvColi strains, we obtained a strong reduction of both proliferative and invasive behaviour of tumour cells and we also confirmed the pivotal role of COX-2 overexpression for the survival of CRC cells. Finally, ex vivo data showed a global anti-inflammatory and anti-tumour effect elicited by COX-2 silencing.

Selective cyclooxygenase-2 (COX-2) silencing mediated by engineered Escherichia coli and RNA Interference induces anti-tumour effects in human colon cancer cells

STRILLACCI, ANTONIO;GRIFFONI, CRISTIANA;LAZZARINI, GIORGIA;VALERII, MARIA CHIARA;DI MOLFETTA, SERENA;RIZZELLO, FERNANDO;CAMPIERI, MASSIMO;TOMASI, VITTORIO;SPISNI, ENZO
2010

Abstract

Colorectal cancer (CRC) has an elevated incidence worldwide and represents one of the most aggressive human tumours. Many experimental data provide the evidence of a strong association between cyclooxygenase-2 (COX-2) enzyme overexpression and colon tumorigenesis. Furthermore, it has been demonstrated that the chronic use of non-steroidal anti-inflammatory drugs (NSAIDs, a class of COX-2 inhibitors), partially protects patients from CRC development and progression. Unfortunately, NSAIDs have been shown to induce severe side effects in chronically treated patients and, therefore, new strategies for selective COX-2 blockade are needed. In this paper we present an innovative COX-2 silencing approach mediated by RNA Interference (RNAi) which is a mechanism we have already described as a powerful tool to knockdown COX-2 protein in CRC cells. In particular, we developed an improved method to gain a highly selective COX-2 silencing in CRC cells by a tumour-dependent expression of anti-COX-2 short hairpin RNA (shCOX-2). Moreover, we efficiently delivered shCOX-2 expressing vectors in CRC cells, in vitro and ex vivo, by using engineered Escherichia coli strains, capable of infecting and invading human tumour cells (InvColi). Combining the highly selective shCOX-2 expression and the delivery of COX-2 silencers mediated by InvColi strains, we obtained a strong reduction of both proliferative and invasive behaviour of tumour cells and we also confirmed the pivotal role of COX-2 overexpression for the survival of CRC cells. Finally, ex vivo data showed a global anti-inflammatory and anti-tumour effect elicited by COX-2 silencing.
BRITISH JOURNAL OF CANCER
A. Strillacci; C. Griffoni; G. Lazzarini; M. C. Valerii; S. Di Molfetta; F.Rizzello; M. Campieri; M. P. Moyer; V. Tomasi; E. Spisni
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/94419
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