Synergistic Tumor Suppression by Coexpression of FHIT and p53 Coincides with FHIT-Mediated MDM2 Inactivation and p53 Stabilization in Human Non-Small Cell Lung Cancer Cells

Abstract

Aberrations of the tumor suppressor genes FHIT and p53 are frequently associated with a wide range of human cancers, including lung cancer. We studied the combined effects of FHIT and p53 proteins on tumor cell proliferation and apoptosis in human non-small cell lung carcinoma (NSCLC) cells in vitro and on tumor growth in animal models by adenoviral vector-mediated cotransfer of wild-type FHIT and p53 genes. We found that the coexpression of FHIT and p53 synergistically inhibited tumor cell proliferation in NSCLC cells in vitro and suppressed the growth of human tumor xenografts in nude mice. Furthermore, we found that this synergistic inhibition of tumor cell growth corresponded with the FHIT-mediated inactivation of MDM2, which thereby blocked the association of MDM2 with p53, thus stabilizing the p53 protein. Our results therefore reveal a novel molecular mechanism consisting of FHITmediated tumor suppression and the interaction of FHIT with other cellular components in the pathways regulating p53 activity. These findings show that combination treatment with synergistic tumor-suppressing gene therapy such as Ad-FHIT and Ad-p53 may be an effective therapeutic strategy for NSCLC and other cancers.

Induction of apoptosis by tumor suppressor FHIT via death receptor signaling pathway in human lung cancer cells

“…A549 was maintained in Ham's F-12 medium with 10% FBS. The construction and production of Ad-FHIT, an adenoviral vector carrying the p53 gene (Ad-p53), and an empty adenoviral vector (Ad-EV) were described previously (9).…”

“…We previously showed that exogenous expression of the wt-FHIT gene induced apoptosis in human NSCLC cells [4,9]. To further characterize the response of NSCLC cells to exogenous expression of FHIT protein and analyze the molecular mechanism of FHIT-mediated apoptosis, we induced overexpression of wt-FHIT by transducing the human NSCLC cell lines H1299 and A549 with Ad-FHIT.…”

“…Inactivation of the FHIT protein plays an important role in the development of several human cancers, including lung cancer [5][6][7]. Several lines of in vitro and in vivo experimental evidence have demonstrated the tumor suppression function of the FHIT gene [8][9][10][11][12]. Exogenous expression of the FHIT gene in 3p14.2-deficient cancer cells induces apoptosis and alters cell cycle kinetics in various types of cancer cells [13][14][15].…”

“…Exogenous expression of the FHIT gene in 3p14.2-deficient cancer cells induces apoptosis and alters cell cycle kinetics in various types of cancer cells [13][14][15]. Also, a previous study implicated the FHIT-induced tumor suppression in FHIT-mediated inactivation of MDM2 and subsequent stabilization of p53 protein in human lung cancer cells [9]. Although the proapoptotic function of FHIT is well documented, the precise molecular mechanism by which FHIT exerts potent tumor suppression activity remains largely unclear.…”

The antitumor activity of TRAIL and IL-24 with replicating oncolytic adenovirus in colorectal cancer

“…Many previous studies have suggested that combination of two therapeutic genes mediated by replication-defective vectors has exerted synergic or compensatory antitumor activity. 29,30 Based on all available data, we decided to evaluate the combined use of ZD55-IL-24 and ZD55-TRAIL and the results are presented.…”