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 α4, α5, α7 subunits nAChRs 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 was 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.

尼古丁是香烟烟雾的主要成瘾成分，虽然它不被认为是致癌的，但它可以根据癌症的类型增强或抑制癌细胞的增殖。尼古丁通过烟碱乙酰胆碱受体 (nAChR) 介导其作用，这些受体在许多不同的神经元和非神经元细胞类型中表达。我们观察到 α4、α5、α7 亚基 nAChRs 在卵巢癌 (OC) 细胞中表达。尼古丁抑制具有TP53突变和野生型KRAS的SKOV3和TOV112D OC细胞的增殖，但不抑制具有KRAS突变和野生型TP53的TOV21G或HEY OC细胞的增殖。暴露于尼古丁 96 小时导致 SKOV3 细胞中激活的细胞外信号调节激酶 (ERK) 和激活的 p38 丝裂原激活蛋白激酶 (MAPK) 的数量显着减少；以及在 TOV112D 细胞中激活的 ERK。此外，混合谱系激酶 3 (MLK​​3) 的 siRNA 敲低或 MEK 抑制显着抑制了 SKOV3 和 TOV112D 的侵袭和球体形成。尼古丁处理减少了 SKOV3 和 TOV112D 球体的侵袭和压实，但没有显着影响球体的形成。此外，SB202190 抑制 p38 可阻止 SKOV3 球体入侵，但 U0126 抑制 MEK 则不能阻止；而 TOV112D 球体入侵被 MEK 抑制减少，但不会被 p38 抑制减少。这些结果表明，尼古丁可以抑制 SKOV3 和 TOV112D OC 细胞的球体侵袭和压实以及增殖；p38 和 ERK MAPK 信号通路是这些反应的重要介质。