The 3p21.3 tumor suppressor NPRL2 plays an important role in cisplatin-induced resistance in human non-small-cell lung cancer cells.
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 -0.677 (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.
Ueda
Kentaro
K
Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Kawashima
Hiroyuki
H
Ohtani
Shoichiro
S
Deng
Wu-Guo
WG
Ravoori
Murali
M
Bankson
Jim
J
Gao
Boning
B
Girard
Luc
L
Minna
John D
JD
Roth
Jack A
JA
Kundra
Vikas
V
Ji
Lin
L
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000008:administration & dosage; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage; D011897:Random Allocation; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D005229:Fatty Acids, Monounsaturated; C492816:NPRL2 protein, human; D009363:Neoplasm Proteins; D000644:Quaternary Ammonium Compounds; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; D002784:Cholesterol; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane; D002945:Cisplatin