Nicotine inhibits MAPK signaling and spheroid invasion in ovarian cancer cells

Exp Cell Res. 2020 Sep 1;394(1):112167. doi: 10.1016/j.yexcr.2020.112167. Epub 2020 Jul 7.


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.

Keywords: Invasion; MAPK; Nicotine; Ovarian cancer; Spheroid.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Carcinoma, Ovarian Epithelial / drug therapy
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Female
  • Humans
  • Imidazoles / pharmacology
  • Nicotine / pharmacology*
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Phosphorylation / drug effects
  • Pyridines / pharmacology
  • Receptors, Nicotinic / drug effects*
  • Receptors, Nicotinic / metabolism
  • Signal Transduction / drug effects*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Imidazoles
  • Pyridines
  • Receptors, Nicotinic
  • Nicotine
  • p38 Mitogen-Activated Protein Kinases
  • 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole