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.