Inhibition of BMP and of TGFß receptors downregulates expression of XIAP and TAK1 leading to lung cancer cell death.

BACKGROUND: Bone morphogenetic proteins (BMP) are embryonic proteins that are part of the transforming growth factor (TGFß) superfamily, which are aberrantly expressed in many carcinomas. Inhibition of BMP receptors with small molecule inhibitors decreases growth and induces death of lung cancer cells, which involves the downregulation of Id1 and Id3 by a Smad dependent mechanism. Developmentally, BMP and TGFß signaling utilizes Smad-1/5 independent mechanisms to stabilize the expression of X-linked inhibitor of apoptosis protein (XIAP) and activate TGFß activated kinase 1 (TAK1), which are known to be potent inhibitors of apoptosis. The role of BMP signaling in regulating XIAP and TAK1 in cancer cells is poorly understood. Furthermore, the interaction between the BMP and TGFß signaling cascades in regulating the activation of TAK1 in cancer cells has not been elucidated. METHODS: Feedback regulation between the BMP and TGFß signaling pathways and their regulation of XIAP, TAK1, and Id1 were examined in lung cancer cells utilizing siRNA and inhibitors targeting BMP type I receptors, inhibitors of BMP and TGFß type I receptors, and an inhibitor of BMP and TGFß type I and type II receptors. RESULTS: We show that upon inhibition of BMP signaling in lung cancer cells, the TGFß signaling cascade is activated. Both the BMP and TGFß pathways activate TAK1, which then increases the expression of Id1. Inhibition of TGFß signaling increased Id1 expression except when BMP signaling is suppressed, which then causes a dose-related decrease in the expression of Id1. Inhibition of both BMP and TGFß signaling enhances the downregulation of TAK1. Our data also suggests that the blockade of the BMP type II receptor enhances the downregulation XIAP, which is important in decreasing the activity of TAK1. Knockdown studies demonstrate that both XIAP and TAK1 regulate the survival of lung cancer cells. CONCLUSIONS: This paper highlights that targeting the BMP and TGFß type I and type II receptors causes a downregulation of XIAP, TAK1, and Id1 leading to cell death of lung cancer cells. Small molecule inhibitors targeting the BMP and TGFß receptors represents a potential novel means to treat cancer patients.

Three Doses of Vitamin D and Cognitive Outcomes in Older Women: A Double-Blind Randomized Controlled Trial.

Vitamin D may affect cognitive performance, but previous studies are either short term or observational. We conducted a randomized controlled trial of vitamin D supplementation on domain-specific cognitive measures in postmenopausal women. Overweight/obese women with serum 25-hydroxyvitamin D (25OHD) levels less than 30 ng/mL were recruited. Vitamin D3 supplementation (600, 2,000, or 4,000 IU/d) was randomly assigned in a double-blinded manner for 1 year. Serum 25-hydroxyvitamin D, osteocalcin (total and undercarboxylated), amyloid beta, parathyroid hormone, and estradiol were analyzed before and after supplementation. Cognitive tests were administered after treatment. The women (58 ± 6 years; body mass index, 30.0 ± 3.5 kg/m2) had a baseline serum 25-hydroxyvitamin D level of 22.6 ± 5.8 ng/mL that increased to 30.2 ± 5.6, 36.0 ± 4.9, and 40.8 ± 7.0 ng/mL in the 600, 2,000, and 4,000 IU/d groups, respectively (p < .001). Participants taking 2,000 IU/d compared to other doses performed better in learning and memory tests (p < .05), yet the 4,000 IU/d group had a slower reaction time compared to the 600 IU/d group. Multiple regression indicated that serum undercarboxylated osteocalcin predicted tasks associated with reaction time and executive function, whereas body mass index and parathyroid hormone negatively predicted reaction time and executive function (p ≤ .01). These data suggest that vitamin D has differential effects on domain-specific cognitive measures and that a higher dose may negatively affect reaction time.