Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase Cα

Lee, Hong Jin; Ji, Yan; Paul, Shiby; Maehr, Hubert; Uskoković, Milan R.; Suh, Nanjoo

doi:10.1158/0008-5472.can-07-1549

Cited by 10 publications

(8 citation statements)

References 51 publications

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“…This effect was lost following LNA-knockdown of miR-1228, which also impaired 1,25D-mediated induction of alkaline phosphatase and osteocalcin, suggesting a key role for miR-1228 in osteoblast differentiation. In bone, vitamin D and analogs are known to modulate intracellular signaling molecules and the synthesis of ligands and receptors for both TGF-β and BMP pathways (45). Regulation of BMP2K protein by miR-1228 therefore provides another level of complexity by which vitamin D is able to interface with the BMP2 pathway.…”

Section: Discussionmentioning

confidence: 99%

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Vitamin D activation of functionally distinct regulatory miRNAs in primary human osteoblasts

Lisse

Chun

Rieger

et al. 2013

Journal of Bone and Mineral Research

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When bound to the vitamin D receptor (VDR), the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D ) is a potent regulator of osteoblast transcription. Less clear is the impact of 1,25D on post-transcriptional events in osteoblasts, such as the generation and action of microRNAs (miRNAs). Microarray analysis using replicate (n = 3) primary cultures of human osteoblasts (HOB) identified human miRNAs that were differentially regulated by > 1.5-fold following treatment with 1,25D (10nM, 6 hrs), which included miRNAs 637 and 1228. RT-PCR analyses showed that the host gene for miR-1228, low density lipoprotein receptor-related protein 1 (LRP1), was co-induced with miR-1228 in a dose-dependent fashion following treatment with 1,25D (0.1 – 10nM, 6hrs). By contrast, the endogenous host gene for miR-637, death-associated protein kinase 3 (DAPK3), was transcriptionally repressed by following treatment with 1,25D. Analysis of two potential targets for miR-637 and miR-1228 in HOB, type IV collagen (COL4A1) and bone morphogenic protein 2 kinase (BMP2K) respectively, showed that 1,25D-mediates suppression of these targets via distinct mechanisms. In the case of miR-637, suppression of COL4A1 appears to occur via decreased levels of COL4A1 mRNA. By contrast, suppression of BMP2K by miR-1228 appears to occur by inhibition of protein translation. In mature HOBs, siRNA inactivation of miR-1228 alone was sufficient to abrogate 1,25D-mediated down regulation of BMP2K protein expression. This was associated with suppression of pro-differentiation responses to 1,25D in HOB, as represented by parallel decrease in osteocalcin and alkaline phosphatase expression. These data show for the first time that the effects of 1,25D on human bone cells are not restricted to classical VDR-mediated transcriptional responses but also involve miRNA-directed post-transcriptional mechanisms.

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Section: Discussionmentioning

confidence: 99%

“…In bone, vitamin D and analogs are known to modulate intracellular signaling molecules and the synthesis of ligands and receptors for both TGF-b and BMP pathways. (45) Regulation of BMP2K protein by miR-1228 therefore provides another level of complexity by which vitamin D is able to interface with the BMP2 pathway.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D activation of functionally distinct regulatory miRNAs in primary human osteoblasts

Lisse

Chun

Rieger

et al. 2013

Journal of Bone and Mineral Research

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“…We have also reported that Gemini vitamin D analogs were shown to activate the bone morphogenetic protein (BMP)/Smad signaling pathway via Ras/PKCα, which mediates the proliferation of the MCF10 breast epithelial cells (48, 49). In this report, we demonstrate for the first time that the Gemini vitamin D analog 0097 activates Smad signaling in vivo in MCF10DCIS.com transplanted tumors (Fig.…”

Section: Discussionmentioning

confidence: 99%

Gemini Vitamin D Analogues Inhibit Estrogen Receptor–Positive and Estrogen Receptor–Negative Mammary Tumorigenesis without Hypercalcemic Toxicity

Lee

Paul

Atalla

et al. 2008

Cancer Prevention Research

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Numerous preclinical, epidemiologic, and clinical studies have suggested the benefits of vitamin D and its analogues for the prevention and treatment of cancer. However, the hypercalcemic effects have limited the use of 1α,25(OH) 2 D 3 , the hormonally active form of vitamin D. To identify vitamin D analogues with better efficacy and low toxicity, we have tested >60 novel Gemini vitamin D analogues with a unique structure of two side chains for growth inhibition of breast cancer cells. Our initial studies found that some Gemini analogues are 5-15 times more active than 1α,25(OH) 2 D 3 in growth inhibition assay. In vivo experiments were designed to study the inhibitory effect of selected Gemini vitamin D analogues against mammary carcinogenesis by using -hexafluoro-19-nor-cholecalciferol] administration inhibited by 60% the NMUinduced mammary tumor burden compared with the NMU-treated control group, but these compounds were devoid of hypercalcemia toxicity. In an ER-negative xenograft model, Gemini 0097 significantly suppressed tumor growth without hypercalcemia toxicity. We found that the inhibitory effect of Gemini 0097 was associated with an increased level of cyclin-dependent kinase inhibitor p21 and the insulin-like growth factor binding protein 3 in both ER-positive and ER-negative mammary tumors. Our results suggest that Gemini vitamin D analogues may be potent agents for the prevention and treatment of both ER-positive and ER-negative breast cancer without hypercalcemia toxicity.In the United States, breast cancer remains the most frequently diagnosed cancer and the second leading cause of cancer death in women according to Cancer Statistics from the American Cancer Society. Because of the complexity and heterogeneity of mammary carcinogenesis (1), many pharmacologic agents have been studied for their effects on the prevention of breast cancer. For example, selective estrogen receptor (ER) modulators such as tamoxifen and raloxifene have achieved significant reduction of breast cancer incidence in women at high risk (2, 3). However, selective ER modulators are not effective in preventing ER-negative breast cancer, which corresponds to at least one third of the breast cancer cases (4). The vitamin D receptor (VDR), a member of the nuclear receptor superfamily, has been suggested as a target for both ER-positive and ER-negative breast cancer prevention (5, 6) because it is present in most breast tumors (4), and VDR ablation in mice was reported to enhance carcinogeninduced formation of mammary tumors (7). These results suggest a role of vitamin D signaling in the regulation of mammary tumorigenesis.The ligand for VDR, 1α,25-dihydroxyvitamin D 3 (1α,25(OH) 2 D 3 ; the key hormone in calcium/phosphate homeostasis) is a hormonally active metabolite synthesized from vitamin D 3 predominantly through hydroxylation by a 25-hydroxylase in the

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“…1α,25(OH) 2 D 3 also inhibited TGF-β1-stimulated EMT and a pro-fibrotic phenotype of lung fibroblasts and epithelial cells [74]. In contrast, 1α,25(OH) 2 D 3 or its analogs increased mRNA levels of BMP2 and BMP6, and activated the BMP signaling in normal and premalignant breast epithelial cells [75,76]. The expression of BMP6 mRNA was also significantly induced by 1α,25(OH) 2 D 3 in prostatic epithelial and breast cancer cells [77].…”

Section: Regulation Of Stem Cell Signaling By Vitamin D In Solid Tumentioning

confidence: 99%

Targeting cancer stem cells in solid tumors by vitamin D

Suh

2015

The Journal of Steroid Biochemistry and Molecular Biology

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Cancer stem cells (CSCs) are a small subset of cells that may be responsible for initiation, progression and recurrence of tumors. Recent studies have demonstrated that CSCs are highly tumorigenic and resistant to conventional chemotherapies, making them a promising target for the development of preventive/therapeutic agents. A single or combination of various markers, such as CD44, EpCAM, CD49f, CD133, CXCR4, ALDH-1 and CD24, were utilized to isolate CSCs fromvarious types of human cancers. Notch, Hedgehog, Wnt, and TGF-β signalingregulate self-renewal and differentiation of normal stem cells andare aberrantly activated in CSCs. In addition, many studies have demonstrated that these stem cell-associated signaling pathways are required for the maintenance of CSCs in differentmalignancies, including breast, colorectal, prostate and pancreatic cancers. Accumulating evidence hasshowninhibitory effects of vitamin D and its analogs on the cancer stem cell signaling pathways, suggesting vitamin D as a potential preventive/therapeutic agent against CSCs.In this review, we summarize recent findings about the roles of Notch, Hedgehog, Wnt, and TGF-β signaling in CSCs as well as the effects of vitamin D on these stem cell signaling pathways.

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Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase Cα

Cited by 10 publications

References 51 publications

Vitamin D activation of functionally distinct regulatory miRNAs in primary human osteoblasts

Vitamin D activation of functionally distinct regulatory miRNAs in primary human osteoblasts

Gemini Vitamin D Analogues Inhibit Estrogen Receptor–Positive and Estrogen Receptor–Negative Mammary Tumorigenesis without Hypercalcemic Toxicity

Targeting cancer stem cells in solid tumors by vitamin D

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