title: SOCS-1 gene delivery cooperates with cisplatin plus pemetrexed to exhibit preclinical antitumor activity against malignant pleural mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis for which an effective therapy remains to be established. This study investigated the therapeutic potential of gene delivery using suppressor of cytokine signaling 1 (SOCS-1), an endogenous inhibitor of intracellular signaling pathways, for the treatment of MPM. We infected MPM cells (MESO-4, H28 and H226) with adenovirus-expressing SOCS-1 vector to examine the effect of SOCS-1 overexpression on MPM cells. We evaluated the antitumor effect of SOCS-1 gene delivery combined with cisplatin plus pemetrexed by cell proliferation, apoptosis and invasion assay. We also investigated the regulation of NF-κB and STAT3 signaling related to apoptotic pathways. Furthermore, we evaluated the inhibition of tumor growth by SOCS-1 gene delivery combined with cisplatin plus pemetrexed in vivo. SOCS-1 gene delivery cooperated with cisplatin plus pemetrexed to inhibit cell proliferation, invasiveness and induction of apoptosis in MPM cells. SOCS-1 regulated NF-κB and STAT3 signaling to induce apoptosis in MESO-4 and H226 cells. Furthermore, SOCS-1 gene delivery cooperated with cisplatin plus pemetrexed to regulate NF-κB signaling and significantly inhibit tumor growth of MPM in vivo. These results suggest that SOCS-1 gene delivery has a potent antitumor effect against MPM and a potential for clinical use in combination with cisplatin plus pemetrexed.
authors.affiliation: Laboratory for Immune Signal, National Institute of Biomedical Innovation, Osaka, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Iwahori
authors.forename: Satoshi
authors.initials: S
authors.lastname: Serada
authors.forename: Minoru
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Barry
authors.initials: B
authors.lastname: Ripley
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nomura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizuguchi
authors.forename: Kazuki
authors.initials: K
authors.lastname: Shimada
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawase
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology; D008654:Mesothelioma / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D000068437:Pemetrexed; D010997:Pleural Neoplasms / Q000473:pathology / Q000628:therapy*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D005971:Glutamates; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; C108944:SOCS1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000068437:Pemetrexed; D006147:Guanine; D007371:Interferon-gamma; D002945:Cisplatin