Cotinine, a major nicotine metabolite, induces cell proliferation on urothelium in vitro and in vivo

Shugo Suzuki, Samuel M. Cohen, Lora L. Arnold, Karen L. Pennington, Hiroyuki Kato, Taku Naiki, Aya Naiki-Ito, Yoriko Yamashita, Satoru Takahashi

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Abstract

Tobacco smoking is a major risk factor for human cancers including urinary bladder carcinoma. In a previous study, nicotine enhanced rat urinary bladder carcinogenesis using a rat urinary bladder two-stage carcinogenesis model. In the present study, nicotine metabolites (cotinine, trans-3’-hydroxy cotinine and N’-nitrosonornicotine) were evaluated in a cell proliferation assay using urinary bladder urothelial cell lines. Cotinine (0.1 to 1 mM) induced the highest cell proliferation compared to the others, including nicotine, in three bladder cancer cell lines (RT4, T24 and UMUC3 cells). By Western blot, cotinine induced phosphorylation of Stat3 and expression of cyclin D1 in UMUC3 cells. The cell proliferation induced by cotinine was blocked by inhibitors of nicotinic receptors (10 nM SR16584 or 10 μM methyllycaconitine citrate) and Stat3 (100 nM stattic). In an in vivo study, cotinine (13, 40 and 120 ppm) in drinking water also induced cell proliferation and simple hyperplasia in urinary bladder and renal pelvis urothelium of rats, but to a lesser degree compared to nicotine (40 ppm). Cytotoxicity detected by scanning electron microscopy and apoptosis in the bladder urothelium were induced by nicotine but not cotinine. These data suggest that cotinine is able to induce urothelial cell proliferation both in vitro and in vivo, and high urinary concentrations may enhance urothelial carcinogenesis.

Original languageEnglish (US)
Article number152325
JournalToxicology
Volume429
DOIs
StatePublished - Jan 15 2020

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Keywords

  • Cotinine
  • cell proliferation
  • nicotine
  • nicotinic acetylcholine receptor (nAChR)
  • urinary bladder carcinogenesis

ASJC Scopus subject areas

  • Toxicology

Cite this

Suzuki, S., Cohen, S. M., Arnold, L. L., Pennington, K. L., Kato, H., Naiki, T., Naiki-Ito, A., Yamashita, Y., & Takahashi, S. (2020). Cotinine, a major nicotine metabolite, induces cell proliferation on urothelium in vitro and in vivo. Toxicology, 429, [152325]. https://doi.org/10.1016/j.tox.2019.152325