Induction of apoptosis and activation of interleukin 1β-converting enzyme/ced-3 protease (caspase-3) and c-Jun NH2-terminal kinase 1 by benzo(a)pyrene

Wei Lei, Rong Yu, Sandhya Mandlekar, A. N.Tony Kong

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Benzo(a)pyrene (BaP), a prototype of polycyclic aromatic hydrocarbons (PAHs), is a potent procarcinogen generated during the combustion of fossil fuels and cigarette smoke in addition to the carcinogenic and mutagenic effects, BaP and other PAHs, including 7,12-dimethylbenz[a]anthracene and 2,3,7,8-tetrachlorodibenzo[p]dioxin, have been shown to induce programmed cell death or apoptosis. However, the molecular mechanisms by which PAlls such as BaP induce apoptosis are not clear. To investigate the molecular events leading to apoptosis induced by BaP, we studied the involvement of the interleukin 1β-converting enzyme (ICE)/Ced-3 family of proteases (caspases) and c-Jun NH2-terminal kinase 1 (JNK1), which have been shown to mediate numerous extracellular stimuli-induced apoptosis. On treatment of mouse Hepa 1c1c7 hepatoma cells with BaP, the induction of apoptosis, as determined by genome digestion, was observed at concentrations of 1-30 μM after 24 h of treatments. Importantly, at the apoptosis-inducing concentrations, BaP also induced the activation of an ICE/Ced-3 cysteine protease caspase-3 but not caspase-1 (ICE). The activation of caspase-3 by BaP preceded apoptosis. Furthermore, a specific inhibitor of caspase-3-like proteases, acetyl-Asp- Glu-Val-Asp-aldehyde, significantly blocked caspase-3 activity and attenuated apoptosis induced by BaP. Treatment with BaP also caused a time- and dose- dependent activation of JNK1 activity. Interestingly, a much lower concentration (5 nM), as well as much earlier kinetics, were observed in JNK1 activation as compared with caspase-3 activation or induction of apoptosis by BaP. In summary, our results demonstrate that BaP induced apoptosis in the mouse hepatoma Hepa1c1c7 cell line via a caspase-dependent pathway, which may be independent of JNK activation.

Original languageEnglish (US)
Pages (from-to)2102-2106
Number of pages5
JournalCancer Research
Issue number10
StatePublished - May 15 1998
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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