title: Plexin A1 signaling confers malignant phenotypes in lung cancer cells.
abstract: Aberrant changes to several signaling pathways because of genetic mutations or increased cytokine production are critical for tumor cells to become malignant. Semaphorin 3A (SEMA3A) acts as a bivalent factor that suppresses or promotes tumor development in different pathological backgrounds. Previously, we showed that SEMA3A positively regulated the proliferative and glycolytic activities of mouse-derived Lewis lung carcinoma (LLC) cells. Plexins A1-A4 (PLXNA1-PLXNA4) are SEMA3A receptors; however, it is not known which subtype is critical for oncogenic SEMA3A signaling. We used LLC cells to investigate the role of PLXNA1 in oncogenic SEMA3A signaling. Using short hairpin RNA-mediated knockdown, we investigated the effects of constitutive inhibition of Plxna1 on cell proliferation, metabolic dependency, and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) sensitivity. We found that Plxna1 knockdown did not affect apoptosis but resulted in decreased cell proliferation and reductions in mRNA expression levels of proliferation-marker genes, such as Ccnd1, Pcna, and Myc. In addition, we found decreased mRNA expression levels of glycolysis-associated genes, such as Pkm2 and Ldha, and decreased lactate production. In contrast, we found no changes in the mRNA expression levels of oxidative phosphorylation-associated genes, such as Cycs, Cox5a, and Atp5g1. We found that Plxna1 knockdown conferred resistance to glucose starvation but increased cytotoxicity to oligomycin. Plxna1 or Sema3a knockdown caused an increased sensitivity to the EGFR-TKIs gefitinib and erlotinib, in Lewis lung carcinoma (LLC) cells. These findings demonstrate that PLXNA1 mediates the acquisition of malignant phenotypes induced by autocrine SEMA3A signaling.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata, Niigata 956-8603, Japan. Electronic address: dyamada@nupals.ac.jp.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamada
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata, Niigata 956-8603, Japan. Electronic address: 11p161n@st.nupals.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata, Niigata 956-8603, Japan. Electronic address: kkawa@nupals.ac.jp.
authors.forename: Kohichi
authors.initials: K
authors.lastname: Kawahara
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata, Niigata 956-8603, Japan. Electronic address: maeda@nupals.ac.jp.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Maeda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D009419:Nerve Tissue Proteins; C492114:Plxna1 protein, mouse; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; D000069347:Erlotinib Hydrochloride; D005947:Glucose; D000077156:Gefitinib
keywords: Drug resistance; Glycolysis; Lung cancer; Plexin A1; Semaphorin 3A