Regulation of apoptosis in adipocytes and breast cancer cells by 1,25-dihydroxyvitamin D3: a link between obesity and breast cancer.
01 Aug 2013-Hormone Molecular Biology and Clinical Investigation (De Gruyter)-Vol. 14, Iss: 3, pp 99-106
TL;DR: The 1,25(OH)2D3-Ca2+ link between obesity and breast cancer supports the rationale to include Ca2+-dependent apoptotic proteases as molecular targets for the discovery of new therapeutic and preventive agents for breast cancer and obesity.
Abstract: Modulation of apoptosis is emerging as a promising strategy for prevention and treatment of breast cancer and obesity because removal of mammary cancer cells and mature adipocytes through this process will result in decreasing tumor size and produce long-term reduction in adipose tissue mass. The hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) triggers apoptosis in breast cancer cells and adipocytes via the induction of the apoptotic Ca2+ signal - a sustained increase in concentration of intracellular Ca2+. This signal acts as an apoptotic initiator that directly recruits Ca2+-dependent apoptotic effectors, calpain and caspase 12, in breast cancer cells and adipocytes. Normal mammary epithelial cells are resistant to 1,25(OH)2D3-induced, Ca2+-mediated apoptosis because the mechanisms regulating Ca2+ in these cells do not sustain Ca2+ increase at the apoptosis-inducing level. Induction of apoptosis with 1,25(OH)2D3 in adipose tissue, particularly in the tumor-surrounding adipose tissue involved in tumor progression, can contribute to the anticancer effects of the hormone. The 1,25(OH)2D3-Ca2+ link between obesity and breast cancer supports the rationale to include Ca2+-dependent apoptotic proteases as molecular targets for the discovery of new therapeutic and preventive agents for breast cancer and obesity; it also supports the recommendation to maintain adequate or increased vitamin D and calcium intakes as one of the possible ways to protect against breast cancer and decrease adiposity.
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TL;DR: The latest findings on the non-classical functions of vitamin D at the cellular/molecular level and its role in complex human diseases are discussed and summarized.
Abstract: The classical function of Vitamin D, which involves mineral balance and skeletal maintenance, has been known for many years. With the discovery of vitamin D receptors in various tissues, several other biological functions of vitamin D are increasingly recognized and its role in many human diseases like cancer, diabetes, hypertension, cardiovascular, and autoimmune and dermatological diseases is being extensively explored. The non-classical function of vitamin D involves regulation of cellular proliferation, differentiation, apoptosis, and innate and adaptive immunity. In this review, we discuss and summarize the latest findings on the non-classical functions of vitamin D at the cellular/molecular level and its role in complex human diseases.
133 citations
Cites background from "Regulation of apoptosis in adipocyt..."
..., showed that 1,25(OH)2D3 induces Ca2+ signal in breast cancer cells and adipocytes, which directly recruits Ca2+-dependent apoptotic effectors, calpain, and caspase 12 to initiate apoptosis [30]....
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TL;DR: Targeting this pathway with vitamin D and Ca supplementation could contribute to the prevention and treatment of obesity, however, this potentially effective and affordable approach needs to be evaluated from a safety point of view.
Abstract: Scope Modulation of apoptosis is emerging as a promising antiobesity strategy because removal of adipocytes through this process will result in reducing body fat. Effects of vitamin D on apoptosis are mediated via multiple signaling pathways that involve common regulators and effectors converging on cellular Ca(2+) . We have previously shown that 1,25-dihydroxyvitamin D3 induces the Ca(2+) signal associated with activation of Ca(2+) -dependent apoptotic proteases in mature adipocytes. In this study, a diet-induced obesity (DIO) mouse model was used to evaluate the role of vitamin D and calcium in adiposity. Methods and results DIO mice fed high vitamin D3 , high Ca, and high D3 plus high Ca diets demonstrated a decreased body and fat weight gain, improved markers of adiposity and vitamin D status (plasma concentrations of glucose, insulin, adiponectin, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, parathyroid hormone (PTH)), but an increased plasma Ca(2+) . High D3 and Ca intakes were associated with induction of apoptosis and activation of Ca(2+) -dependent apoptotic proteases, calpain and caspase-12, in adipose tissue of DIO mice. The combination of D3 plus Ca was more effective than D3 or Ca alone in decreasing adiposity. Conclusion The results imply that high vitamin D and Ca intakes activate the Ca(2+) -mediated apoptotic pathway in adipose tissue. Targeting this pathway with vitamin D and Ca supplementation could contribute to the prevention and treatment of obesity. However, this potentially effective and affordable approach needs to be evaluated from a safety point of view.
96 citations
Cites background from "Regulation of apoptosis in adipocyt..."
...Apoptosis is the main mechanism for regulating cell number in many tissues [4, 18]....
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TL;DR: An overview of the calcium and vitamin D disturbances occurring in DM is provided and the underlying mechanisms are described to help indicate potential pathophysiology-based precautionary and therapeutic approaches and contribute to lowering the incidence of DM.
Abstract: Diabetes mellitus (DM) is becoming a lifestyle-related pandemic disease. Diabetic patients frequently develop electrolyte disorders, especially diabetic ketoacidosis or nonketotic hyperglycemic hyperosmolar syndrome. Such patients show characteristic potassium, magnesium, phosphate, and calcium depletion. In this review, we discuss a homeostatic mechanism that links calcium and DM. We also provide a synthesis of the evidence in favor or against this linking mechanism by presenting recent clinical indications, mainly from veterinary research. There are consistent results supporting the use of calcium and vitamin D supplementation to reduce the risk of DM. Clinical trials support a marginal reduction in circulating lipids, and some meta-analyses support an increase in insulin sensitivity, following vitamin D supplementation. This review provides an overview of the calcium and vitamin D disturbances occurring in DM and describes the underlying mechanisms. Such elucidation will help indicate potential pathophysiology-based precautionary and therapeutic approaches and contribute to lowering the incidence of DM.
49 citations
Cites background from "Regulation of apoptosis in adipocyt..."
...the paracrine and autocrine modes of action of 1,25(OH)2D3 appear to be important in several cell types, including adipocytes and secretory cells in the pancreas, duodenum and kidney [24,25,27,48]....
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TL;DR: The 1,25(OH)2D3 – cellular Ca2+ – apoptosis link in cancer and obesity supports the rationale to include vitamin D compounds modulating intracellular Ca2 + and Ca2-dependent apoptotic proteases as promising targets for discovery of new therapeutic and preventive agents for cancer and Obesity.
Abstract: Low vitamin D status has been associated with increased risk of several cancers and obesity; concurrently, obesity and cancer have been linked to impaired vitamin D status. In both cancer and obesity, selective elimination of cancer cells and adipocytes can result in decreasing tumor size and a long-term reduction in adipose tissue mass. These effects can be achieved through induction of apoptotic cell death. The vitamin D-derived hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) triggers apoptosis in epithelial cancer cells and mature adipocytes via induction of apoptotic Ca2+ signal - a sustained, prolonged increase in concentration of intracellular Ca2+. This Ca2+ signal functions as an apoptotic initiator that directly recruits apoptotic effectors, Ca2+-dependent proteases, in cancer cells and adipocytes. The 1,25(OH)2D3 - cellular Ca2+ - apoptosis link in cancer and obesity supports the rationale to include vitamin D compounds modulating intracellular Ca2+ and Ca2+-dependent apoptotic proteases as promising targets for discovery of new therapeutic and preventive agents for cancer and obesity. The concept of maintaining an increased vitamin D status for protecting against cancer and decreasing adiposity also warrants further evaluation.
32 citations
Cites background from "Regulation of apoptosis in adipocyt..."
...The studies reviewed here have identified the novel apoptotic pathway in epithelial cancer cells and mature adipocytes, which is regulated by 1,25(OH)2D3: sustained increase in [Ca]i → μ-calpain activation → caspase-12 activation → apoptosis, and indicated that the 1,25(OH)2D3activated apoptotic molecular targets are Ca2+-dependent calpain and Ca2+/calpain-dependent caspase-12 (Figure 1) [4]....
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...Cancer and obesity can arise as a consequence of dysregulation of common endocrine, paracrine, and intracellular signaling pathways determining the fate of both cancer cells and adipocytes [4, 6, 11, 21]....
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...The Ca2+-dependent calpains and caspases appear to be primary Ca2+-activated apoptotic effectors [4, 6, 13, 44]....
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...The causal links between vitamin D status and specific diseases (except vitamin D-deficient rickets/osteomalacia and inherited vitamin D receptor/vitamin D metabolism disorders) have yet to be identified, although the increased risk of obesity and several cancers have been reported with vitamin D deficiency and insufficiency [1, 3, 4, 6, 11]....
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...The mechanism of 1,25(OH)2D3-induced, Ca2+-mediated apoptosis in cancer cells includes a sustained increase in [Ca]i associated with activation of the Ca2+dependent protease, μ-calpain, followed by activation of Ca2+/calpain-dependent caspase-12 and, probably, other effector caspases (caspase-3) [4, 6, 13, 33, 36]....
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TL;DR: The findings imply that vitamin D may contribute to the prevention of obesity and obesity-related diseases and that the mechanism of the anti-obesity effect of 1,25(OH)2D3 includes induction of Ca2+-mediated apoptosis in adipocytes.
Abstract: The role of vitamin D in obesity appears to be linked to vitamin D insufficient/deficient status. However, mechanistic understanding of the role of vitamin D in obesity is lacking. We have shown earlier that the vitamin D hormonal form, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), induces cell death by apoptosis in mature adipocytes. This effect of the hormone is mediated by the cellular Ca2+ signaling pathway: a sustained increase of intracellular (cytosolic) Ca2+ concentration followed by activation of Ca2+-dependent initiators and effectors of apoptosis. In recent animal studies, we demonstrated that low vitamin D status is observed in diet-induced obesity (DIO). High intake of vitamin D3 in DIO decreased the weight of white adipose tissue and improved biomarkers related to adiposity and Ca2+ regulation. The anti-obesity effect of vitamin D (1,25(OH)2D3) in DIO was determined by the induction of Ca2+-mediated apoptosis in mature adipocytes executed by Ca2+-dependent apoptotic proteases (calpains and caspases). Thus, a high intake of vitamin D in obesity increases vitamin D nutritional status and normalizes vitamin D hormonal status that is accompanied by the reduction of adiposity. Overall, our findings imply that vitamin D may contribute to the prevention of obesity and obesity-related diseases and that the mechanism of the anti-obesity effect of 1,25(OH)2D3 includes induction of Ca2+-mediated apoptosis in adipocytes.
24 citations
Cites background from "Regulation of apoptosis in adipocyt..."
...Cellular Ca2+ signaling in adipocytes is critical among the signaling pathways linked to obesity [7,13,14], and this signaling is also a main target of the Ca2+ regulatory hormone 1,25(OH)2D3 [1,2,4]....
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...Extra-renal production of 1,25(OH)2D3 utilizes 25(OH)D3 in situ, but it does not appear to contribute to maintaining the circulating 1,25(OH)2D3 level and the possible involvement of such production in paracrine/autocrine regulation of cellular functions is not clear [6,7]....
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...The Ca2+-dependent calpains and caspases appear to be the primary Ca2+-activated apoptotic effectors [7,8,14,29]....
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References
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"Regulation of apoptosis in adipocyt..." refers background in this paper
...Induction of apoptosis is considered as an effective approach for cancer treatment, but apoptotic molecular targets have not been conclusively identified in breast cancer cells [13, 18]....
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Journal Article•
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"Regulation of apoptosis in adipocyt..." refers background in this paper
...Dysregulation of apoptosis underlies the pathophysi ology of proliferative disorders [8, 13, 16]....
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