Role of Nongenomic Activation of Phosphatidylinositol 3-kinase/Akt and Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase/Extracellular Signal-regulated Kinase 1/2 Pathways in 1,25d3-mediated Apoptosis in Squamous Cell Carcinoma Cells.
From: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14201, USA.
Cancer research
- Publish Date: Aug 2006
- ISSN: 1538-7445
- Volume: 66
- Issue: 16
- Pages: 8131-8
- Medium: Internet
- Language: English
- Citation (JAMA): Ma Yingyu, Yu Wei-Dong, Kong Rui-Xian, et al. Role of Nongenomic Activation of Phosphatidylinositol 3-kinase/Akt and Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase/Extracellular Signal-regulated Kinase 1/2 Pathways in 1,25d3-mediated Apoptosis in Squamous Cell Carcinoma Cells.. Cancer Res. Aug 2006;66:8131-8
Abstract
Vitamin D is a steroid hormone that regulates calcium homeostasis and bone metabolism. The active form of vitamin D [1 alpha,25-dihydroxyvitamin D(3) (1,25D3)] acts through both genomic and nongenomic pathways. 1,25D3 has antitumor effects in a variety of cancers, including colorectal, prostate, breast, ovarian, and skin cancers. 1,25D3 exerts growth-inhibitory effects in cancer cells through the induction of apoptosis, cell cycle arrest, and differentiation. The mechanisms regulating 1,25D3-induced apoptosis remain unclear. We investigated the role of nongenomic signaling in 1,25D3-mediated apoptosis in squamous cell carcinoma (SCC) cells. 1,25D3 induced rapid and sustained activation of phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) 1/2 pathways in SCC cells. These effects were nongenomic: they occurred rapidly and were not inhibited by cycloheximide or actinomycin D. To examine whether the nongenomic activation of Akt and ERK1/2 plays a role in 1,25D3-mediated apoptosis, the expression of Akt or ERK1/2 was reduced by small interfering RNA (siRNA). siRNA-Akt significantly enhanced 1,25D3-induced apoptosis as indicated by increased levels of Annexin V-positive cells and increased sub-G(1) population and DNA fragmentation. In contrast, siRNA-ERK1/2 had no effects on 1,25D3-induced apoptosis. In addition, siRNA-Akt transfection followed by 1,25D3 treatment induced apoptosis much sooner than 1,25D3 alone. siRNA-Akt and 1,25D3 induced caspase-10 activation, suppressed the expression of c-IAP1 and XIAP, and promoted 1,25D3-induced caspase-3 activation. These results support a link between 1,25D3-induced nongenomic signaling and apoptosis. 1,25D3 induces the activation of phosphatidylinositol 3-kinase/Akt, which suppresses 1,25D3-mediated apoptosis and prolongs the survival of SCC cells.
Mesh Headings (Keywords): 1-Phosphatidylinositol 3-Kinase, Animals, Apoptosis, Calcitriol, Carcinoma, Squamous Cell, Cell Adhesion, Cell Line, Tumor, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, Mice, Mitogen-Activated Protein Kinases, Proto-Oncogene Proteins c-akt, RNA, Small Interfering, Transfection
Check for Full Text / PubMed Unique Identifier (PMID): 16912191
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