The 3p21.3 Tumor Suppressor NPRL2 Plays an Important Role in Cisplatin-Induced Resistance in Human Non–Small-Cell Lung Cancer Cells

Abstract

NPRL2 is one of the novel candidate tumor suppressor genes identified in the human chromosome 3p21.3 region. The NPRL2 has shown potent tumor suppression activity in vitro and in vivo and has been suggested to be involved in DNA mismatch repair, cell cycle checkpoint signaling, and regulation of the apoptotic pathway. In this study, we analyzed the endogenous expression of the NPRL2 protein and the cellular response to cisplatin in 40 non-small-cell lung cancer cell lines and found that expression of NPRL2 was significantly and reciprocally correlated to cisplatin sensitivity, with a Spearman correlation coefficient of À0.677 (P < 0.00001). Exogenously introduced expression of NPRL2 by N-[1-(2,3-dioleoyloxyl)propyl]-NNN-trimethylammoniummethyl sulfate: cholesterol nanoparticle-mediated gene transfer significantly resensitized the response to cisplatin, yielding a 40% greater inhibition of tumor cell viability and resulting in a 2-to 3-fold increase in induction of apoptosis by activation of multiple caspases in NPRL2-transfected cells compared with untransfected cells at an equal dose of cisplatin. Furthermore, a systemic treatment with a combination of NPRL2 nanoparticles and cisplatin in a human H322 lung cancer orthotopic mouse model significantly enhanced the therapeutic efficacy of cisplatin and overcame cisplatin-induced resistance (P < 0.005). These findings implicate the potential of NPRL2 as a biomarker for predicting cisplatin response in lung cancer patients and as a molecular therapeutic agent for enhancing response and resensitizing nonresponders to cisplatin treatment.

Evaluation of the 3p21.3 tumour-suppressor gene cluster

“…Moreover, in these cells restoration of NPR2L expression enhanced or resensitized the response to cisplatin in originally cisplatin-sensitive and cisplatin-resistant NSCLC tumour cells, respectively. The efficacy of re-expressing NPR2L in combination with cisplatin treatment was also demonstrated on in vivo tumour growth in an orthotopic mouse model of human NSCLC (Ueda et al, 2006). In this system, NPR2L expression in NSCLC tumour cells was reactivated in vivo by systemic i.v.…”

“…One of the most intriguing studies of NPR2L thus far identified a correlation between the level of expression of NPR2L in tumours and sensitivity to the DNA damaging anticancer drug cisplatin (Ueda et al, 2006). NPR2L has highly conserved orthologues in several species including yeast.…”

“…The observation that NPR2L expression is an accurate prognostic indicator of lung cancer cisplatin sensitivity and that its re-expression may re-sensitize nonresponders to cisplatin (Ueda et al, 2006) may also be of significant clinical value. Inactivation of this gene by 3 0 deletions and missense mutations occurs at a moderate frequency in some cancers.…”

Enhancement of antitumor activity of cisplatin in human lung cancer cells by tumor suppressor FUS1

“…24 The transfection efficiency was assessed by a parallel transfection with a green fluorescent protein (GFP)-expressing plasmid vector. The transfection efficiency was in the range of 40 to 60% in those cell lines.…”

“…An orthotopic lung tumor xenograft mouse model of human NSCLC H322, as described previously, 24 was used to evaluate the combined effect of systemic administration of the FUS1-nanoparticles and CDDP on inhibition of tumor growth in vivo. These mice were randomly divided into five treatment groups (five mice per group) as follows: (i) LacZ; (ii) wt-FUS1; (iii) CDDP; (iv) LacZ plus CDDP and (v) wt-FUS1 plus CDDP.…”