Alterations in the activity and expression of serine/threonine protein phosphatases during ATRA-induced apoptosis of human breast cancer cells

SB Omay, MD, PhD,UA Sanli,MD,R Uslu, MD,VC Sezgin, MD, B Karabulut, MD, N Selvi, Msc, HH Aydin, MD, G Saydam, MD, E Goker, MD, F Buyukkececi, MD

Department of Hematology-Oncology Ege University Medical School, Bornova Izmir Turkey

Retinoids, exert different effects on malignant cells with various phenomena. While they can induce differentiation on leukemic cells, they have cytotoxic effects on various cancer cells. However, underlying mechanisms of these effects are not clear. There are data related to the role of protein phosphatases during retinoid-induced leukemic cell differentiation. Protein phosphatases are responsible for the regulation of phosphorylation status of the cells controlling the signals activated by protein kinases. In this study, we investigated the effect of ATRA on MCF-7 human breast cancer cell line. ATRA-induced cytotoxicity is evidenced by apoptotic mechanisms revealed by mono-oligo nucleosome assay. However during ATRA-induced apoptosis of MCF-7 cells, a significant decrease in the activity of serine/threonine phosphatases 2A, 2B, and 2C occurred. The decreased activity of PP2A correlated with the up-regulation of PP2A catalytic and PP2A B gamma, B alpha regulatory subunits. The decrease in the activity of PP2B correlated with down-regulation of PP2B catalytic and the upregulation of PP2B regulatory subunit expression. In addition, there is up-regulation in PP4C and down-regulation in PP2C alpha/beta subunits protein expression during apoptotic process. We strongly suggest that ATRA-induced apoptosis of MCF-7 cells are significantly related to the phosphorylation dynamics. Our findings open a new window in the future treatment of breast cancer.

KEY WORDS: Protein phosphatases, all-trans retinoic acid, breast cancer, apoptosis.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Apoptosis - Molecular Mechanisms.