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PI-3K and Akt are mediators of AP-1 induction by 5-MCDE in mouse epidermal Cl41 cells
Jingxia Li1, Haobin Chen, Moon-Shong Tang
1Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Rd., Tuxedo, NY 10987, USA.
Abstract:
5-Methylchrysene has been found to be a complete carcinogen in laboratory animals. However, the tumor promotion effects of (+/-)-anti-5-methylchrysene-1,2-diol-3,4-epoxide (5-MCDE) remain unclear. In the present work, we found that 5-MCDE induced marked activator protein-1 (AP-1) activation in Cl41 cells. 5-MCDE also induced a marked activation of phosphatidylinositol 3-kinase (PI-3K). Inhibition of PI-3K impaired 5-MCDE-induced AP-1 transactivation, suggesting that PI-3K is an upstream kinase involved in AP-1 activation by 5-MCDE. Furthermore, we found that Akt is a PI-3K downstream mediator for 5-MCDE-induced AP-1 transactivation, whereas another PI-3K downstream kinase, p70(S6K), was not involved in AP-1 activation by 5-MCDE. Moreover, inhibition of Akt activation blocked 5-MCDE-induced activation of extracellular signal-regulated protein kinases (ERKs) and c-Jun NH(2)-terminal kinases (JNKs), whereas it did not affect p38K activation. Consistently, overexpression of a dominant-negative mutant of ERK2 or JNK1 blocked the AP-1 activation by 5-MCDE. These results demonstrate that 5-MCDE is able to induce AP-1 activation, and the AP-1 induction is specifically through a PI-3K/Akt-dependent and p70(S6K)-independent pathway.
Insights
The carcinogen 5-methylchrysene diol epoxide (5-MCDE) activates activator protein-1 (AP-1) via the phosphatidylinositol 3-kinase (PI-3K)/Akt pathway. This pathway is crucial for 5-MCDE-induced AP-1 activation, independent of p70(S6K).
Area of Science:
- Biochemistry
- Molecular Biology
- Carcinogenesis
Background:
- 5-Methylchrysene is a known carcinogen in animals.
- The specific tumor promotion mechanisms of its metabolite, (+/-)-anti-5-methylchrysene-1,2-diol-3,4-epoxide (5-MCDE), are not fully understood.
- Investigating the molecular pathways involved in 5-MCDE's action is crucial for understanding its carcinogenic potential.
Purpose of the Study:
- To elucidate the signaling pathways by which 5-MCDE induces activator protein-1 (AP-1) activation.
- To determine the role of phosphatidylinositol 3-kinase (PI-3K) and its downstream effectors in 5-MCDE-mediated AP-1 induction.
- To identify specific kinases involved in the 5-MCDE signaling cascade.
Main Methods:
- Utilized Cl41 cells to study 5-MCDE effects.
- Assessed AP-1 activation using reporter assays.
- Investigated the involvement of PI-3K, Akt, p70(S6K), extracellular signal-regulated protein kinases (ERKs), and c-Jun NH(2)-terminal kinases (JNKs) through inhibition and overexpression studies.
Main Results:
- 5-MCDE induced significant AP-1 activation in Cl41 cells.
- 5-MCDE treatment led to marked activation of PI-3K.
- Inhibition of PI-3K and Akt, but not p70(S6K), impaired 5-MCDE-induced AP-1 activation.
- Akt activation was necessary for 5-MCDE-induced activation of ERKs and JNKs, but not p38K.
- Overexpression of dominant-negative ERK2 or JNK1 blocked 5-MCDE-induced AP-1 activation.
Conclusions:
- 5-MCDE induces AP-1 activation through a specific signaling pathway.
- The pathway involves PI-3K and its downstream kinase Akt.
- This PI-3K/Akt-dependent pathway, independent of p70(S6K), mediates 5-MCDE-induced AP-1 activation, involving ERKs and JNKs.
