Involvement of stress activated protein kinases (JNK and p38) in 1,25 dihydroxyvitamin D3-induced breast cell death

• Published in: Steroids Vol. 75; no. 13-14; pp. 1082 - 1088
• Main Authors: BROSSEAU, C. M, PIRIANOV, G, COLSTON, K. W
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier 12.12.2010
• Subjects: Biological and medical sciences; Breast Neoplasms - enzymology; Breast Neoplasms - pathology; Calcitriol - pharmacology; Cell Death - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Enzyme Activation - drug effects; Fundamental and applied biological sciences. Psychology; Gynecology. Andrology. Obstetrics; Humans; JNK Mitogen-Activated Protein Kinases - metabolism; Mammary gland diseases; MAP Kinase Signaling System - drug effects; Medical sciences; p38 Mitogen-Activated Protein Kinases - metabolism; Stress, Physiological - drug effects; Tumors; Vertebrates: endocrinology; Mitogen-activated protein kinases (MAPK); Breast disease; Enzyme; Steroid hormone; Cholecalciferol(1,25-dihydroxy); Stress-activated kinase; Transferases; Mitogen-activated protein kinase; 1,25 dihydroxyvitamin D; Breast cancer; Malignant tumor; terminal kinase; Protein; Micronutrient; Mammary gland diseases; Vitamin D; Cell death; c-Jun NH; Cancer
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2010.07.007

It has been previously demonstrated that 1,25 dihydroxyvitamin D(3) (1,25-D(3)) exerts inhibitory effects in breast cancer cells. The aim of this study was to determine whether mitogen-activated protein kinase (MAPK) pathways are associated with 1,25-D(3)-induced cell death in breast cancer. We used three breast cell lines which have different sensitivities to 1,25-D(3) treatment. Non-malignant MCF-12A cells were more sensitive to 1,25-D(3) treatment than malignant MCF-7 cells (growth inhibition IC(50) 75 nM vs. 100 nM, p<0.001) while malignant MDA-MB-231 cells were resistant. Moreover, 1,25-D(3)-induced apoptosis was caspase-dependent in MCF-12A cells and caspase-independent in MCF-7 cells. Following MAPK activation analysis, we found a significant activation of JNK in MCF-12A cells and malignant MCF-7 cells in response to 1,25-D(3) treatment. Furthermore, 1,25-D(3) treatment stimulated p38 activity in MCF-12A cells and in MCF-7 cells. ERK1/2 activity was unaffected by 1,25-D(3) treatment in all breast cells. Importantly, no increased MAPK activity was observed in MDA-MB-231 breast cancer cells which displayed resistance to 1,25-D(3)-induced apoptosis. Utilising specific pharmacological inhibitors of JNK and p38, it was demonstrated that MCF-12A and MCF-7 cells were protected from death induced by 1,25-D(3). These results implicate JNK and p38 signalling in 1,25-D(3)-induced cancer breast cell death.