Progesterone inhibits the proliferation of normal breast epithelial cells as well as breast cancer cells. The molecular mechanisms of this inhibition are not fully understood. The purpose of this study was to investigate the capacity of progesterone to induce apoptosis and to alter the activity of a key regulator of cell growth and differentiation, the Akt protein. We show here that (i) growth inhibition of breast cancer cells by progesterone is due to the induction of cell differentiation and not to apoptosis; (ii) progesterone activates the PI3-kinase/Akt pathway as shown by the increase in the phosphorylation of Akt protein; (iii) inhibiting PI3-kinase/Akt pathway with LY294002 causes stimulation of apoptosis; and (v) progesterone enhances LY294002 induced-growth inhibition and apoptosis. These results suggest that progesterone may protect breast cancer cells from apoptosis by altering PI3-kinase activity and that MCF-7 cells become more sensitive to progesterone and die by apoptosis upon inhibition of the PI3-kinase/Akt pathway.

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Background: Imbalance between protein synthesis and endoplasmic reticulum (ER) capacity to modify and fold proteins lead to the accumulation of unfolded proteins resulting in ER stress and apoptosis. Chaperones are major defense molecules assisting in protein folding, transport, and cellular signaling. ER stress plays a major role in the pathogenesis of diabetes mellitus (DM) and its complications, e.g., diabetic cataract. In the present investigation, the chemical chaperones 4-phenylbutyric acid (4-PBA), tauroursodeoxycholic acid (TUDCA), and trimethylamine N-oxide (TMAO) are used as potential therapeutic agents for alleviation of DM-induced ER stress and diabetic cataract in rats. Animals are subjected to biochemical analysis of blood and lenses for ER stress and apoptosis markers. Moreover, ophthalmologic examination and histopathologic examination of the lenses were done to confirm the results. Results: Both ophthalmic and lens histopathologic examination revealed that treatment with 4-PBA and TUDCA retarded the occurrence of cataract markedly. Whereas, treatment with TMAO caused a partial improvement of cataract. Moreover, biochemical tests showed that both 4-PBA and TUDCA produced a remarkable improvement in the ER marker levels (VEGF and caspase-12), GSH, MDA, TAC levels in lens tissues. On the other hand, TMAO had no significant effect on these parameters. However, Western blot analysis of lens homogenates showed a suppressed expression of GRP78 and CHOP after treatment with 4-PBA, TUDCA, and TMAO. Moreover, all treated groups showed a significant improvement of lens soluble proteins and their UV spectra absorption. A significant improvement in fasting blood sugar, GSH, serum MDA, and TAC were noted in all treated groups. 4-PBA produced a significant decrease in insulin resistance, whereas TUDCA and TMAO showed insignificant change. Conclusion: The present research found that the tested chaperones could be used as a therapeutic approach for clinically relevant disorders featuring ER dysfunction such as DM and for reducing its complications in the eye mainly cataract. However, TUDCA and 4-PBA were found to have a more potential efficacy in reducing most of the tested parameters as compared to TMAO.

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