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Nicotine inhibits MAPK signaling and spheroid invasion in ovarian cancer cells.

ABSTRACT: Nicotine is the major addictive component of cigarette smoke and although it is not considered carcinogenic, it can enhance or inhibit cancer cell proliferation depending on the type of cancer. Nicotine mediates its effects through nicotinic acetylcholine receptors (nAChRs), which are expressed in many different neuronal and non-neuronal cell types. We observed that the nAChR α4, α5, α7 subunits were expressed in ovarian cancer (OC) cells. Nicotine inhibited the proliferation of SKOV3 and TOV112D OC cells, which have TP53 mutation and wild-type KRAS, but did not inhibit the proliferation of TOV21G or HEY OC cells, which have KRAS mutation and wild-type TP53. Exposure to nicotine for 96 h led to a significant reduction in the amounts of activated extracellular signal-regulated kinase (ERK) and activated p38 mitogen-activated protein kinases (MAPKs) in SKOV3 cells, and in activated ERK in TOV112D cells. In addition, SKOV3 and TOV112D invasion and spheroid formation were substantially inhibited by siRNA knockdown of mixed lineage kinase 3 (MLK3), or MEK inhibition. Nicotine treatment reduced SKOV3 and TOV112D spheroid invasion and compaction but did not significantly affect spheroid formation. Furthermore, SKOV3 spheroid invasion was blocked by p38 inhibition with SB202190, but not by MEK inhibition with U0126; whereas TOV112D spheroid invasion was reduced by MEK inhibition, but not by p38 inhibition. These results indicate that nicotine can suppress spheroid invasion and compaction as well as proliferation in SKOV3 and TOV112D OC cells; and p38 and ERK MAPK signaling pathways are important mediators of these responses.

SUBMITTER: Harmych SJ

PROVIDER: S-EPMC7434703 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Epithelial ovarian cancer (EOC) is still a major gynecologic problem with poor 5 year survival rate due to distance metastases, despite routine surgery and chemotherapy. The precise underlying molecular mechanisms that trigger EOC migration and invasion are unclear. Recent studies suggest that the expression of microRNAs is widely dysregulated in ovarian cancer; and that they have evolved into tumorigenic processes, including cell proliferation, apoptosis and motility. METHODS: The expression of miR-124 was assessed in clinical ovarian cancer specimens and cell lines using miRNA qRTPCR. The function of miR-124 on cell migration and invasion was confirmed in vitro through wound healing assay and transwell assay. Luciferase reporter assay was used to confirm target associations. RESULTS: We showed that miR-124 is down-regulated in ovarian cancer specimens as well as in cell lines; and that low-level expression of miR-124 is much lower in highly metastatic ovarian cancer cells and tissues. Meantime, overexpression of miR-124 dramatically inhibits the motility of ovarian cancer cells in vitro and substantially suppresses the protein expression of SphK1, reported as an invasion and metastasis-related gene in human cancers, whose expression is markedly increased in both ovarian cancer cell lines and clinical samples, particularly in two highly metastasis cells, SKOV3-ip and HO8910pm as well as metastatic ovarian tumor tissues. Furthermore, SphK1 is identified as a direct target of miR-124, and knock-down of SphK1 in ovarian cancer cells, SKOV3-ip and HO8910pm, could mimic the inhibition of migration and invasion by miR-124, while re-introduction of SphK1 abrogates the suppression of motility and invasiveness induced by miR-124 in both cell lines. CONCLUSIONS: Our studies suggest a protective role of miR-124 in inhibition of migration and invasion in the molecular etiology of ovarian cancer, and a potentially novel application of miR-124 in the regulation of migration and invasion in EOC.

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Nicotine inhibits MAPK signaling and spheroid invasion in ovarian cancer cells.

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