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.
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.
Oh
Young-Il
YI
Department of Veterinary Physiology, College of Veterinary Medicine, Chonbuk National University, Duk-Jin Dong 1 Ga 664-14, Jeonju City, Chonbuk, South Korea.
Kim
Jong-Hoon
JH
Kang
Chang-Won
CW
D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000378:metabolism* / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D014212:Tretinoin; D007334:Insulin-Like Growth Factor I; D051745:Protein Kinase C-delta