It is known that all-trans retinoic acid (RA) is a useful therapeutic anticancer agent in breast cancer that acts by inducing apoptosis and growth inhibition. Insulin-like growth factor-I (IGF-I) is also known to be a growth hormone that plays an important role in cell proliferation and apoptosis. We examined the relationships between RA-induced protein kinase C (PKC)-delta, the secretion and synthesis of IGF-I, and oxidative stress. RA at 10(-8)M and 10(-7)M increased PKC-delta phosphorylation (the ratio of phosphorylated to total PKC-delta) (p<0.05) and decreased the secretion and synthesis of IGF-I (p<0.05) compared to control, with the effects peaking for treatment with 10(-7)M RA for 72h. The silencing of PKC-delta prevented the RA-induced inhibition of the secretion and synthesis of IGF-I and cell viability (p<0.05). Application of 10(- 7)M RA for 72h increased the level of thiobarbituric-acid-reactive substances and the expression of inducible nitric oxide synthase relative to control (p<0.05). These increases were blocked by suppressing PKC-delta and by pretreatment with the antioxidants glutathione and diphenyleneiodonium (p<0.05). These antioxidants also reversed the RA-induced inhibition of the secretion and synthesis of IGF-I and cell viability to control levels (p<0.05). The effects of suppressing IGF-I demonstrate that IGF-I plays a critical role in the RA-induced inhibition of the cell viability. These results indicate that the anticancer effects of RA are mediated by inhibition of the secretion and synthesis of IGF-I, and involve a PKC-delta-dependent mechanism, and they provide evidence of an interaction between PKC-delta and reactive oxygen species.
Oxidative stress in MCF-7 cells is involved in the effects of retinoic acid-induced activation of protein kinase C-delta on insulin-like growth factor-I secretion and synthesis