Antiproliferative effect of a vitamin D3 analog, EB1089, on HL-60 cells by the induction of TGF-β receptor

Jung, Chul Won; Kim, Eun S.; Seol, Jae Goo; Park, Woo H.; Lee, Sang Jin; Kim, Byoung K.; Lee, Young Yiul

doi:10.1016/s0145-2126(99)00136-8

Cited by 30 publications

(12 citation statements)

References 34 publications

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“…8 In HL-60 cells, the Vit D 3 analog EB1089 has been shown to induce expression of both TGF-␤ receptors and TGF-␤ ligand, and its antiproliferative activity is blocked by a TGF-␤-neutralizing antibody. 45 Our data now extend these studies and show that in HL-60 cells, the ability of Vit D 3 to phosphorylate Smad2/3 ( Figure 5C) and to stimulate monocytic differentiation can be blocked by neutralizing antibodies to TGF-␤ ( Table 2), suggesting that Vit D 3 acts indirectly by activating signaling from either autocrine or paracrine (exogenous) TGF-␤ in these cells. Moreover, these data also show that reduction in levels of Smad2/3 phosphorylation is sufficient to reduce the commitment of these cells to differentiate to monocytes, even in the absence of changes in the levels of phosphatases.…”

Section: Discussionsupporting

confidence: 78%

Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF-β and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells

Cao

Flanders

Bertolette

et al. 2003

Blood

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We have investigated the role of Smad family proteins, known to be important cytoplasmic mediators of signals from the transforming growth factor–β (TGF-β) receptor serine/threonine kinases, in TGF-β–dependent differentiation of hematopoietic cells, using as a model the human promyelocytic leukemia cell line, HL-60. TGF-β–dependent differentiation of these cells to monocytes, but not retinoic acid–dependent differentiation to granulocytes, was accompanied by rapid phosphorylation and nuclear translocation of Smad2 and Smad3. Vitamin D3 also induced phosphorylation of Smad2/3 and monocytic differentiation; however the effects were indirect, dependent on its ability to induce expression of TGF-β1. Simultaneous treatment of these cells with TGF-β1 and all-trans-retinoic acid (ATRA), which leads to almost equal numbers of granulocytes and monocytes, significantly reduced the level of phospho–Smad2/3 and its nuclear accumulation, compared with that in cells treated with TGF-β1 alone. TGF-β1 and ATRA activate P42/44 mitogen-activated protein (MAP) kinase with nearly identical kinetics, ruling out its involvement in these effects on Smad phosphorylation. Addition of the inhibitor-of-protein serine/threonine phosphatases, okadaic acid, blocks the ATRA-mediated reduction in TGF-β–induced phospho-Smad2 and shifts the differentiation toward monocytic end points. In HL-60R mutant cells, which harbor a defective retinoic acid receptor–α (RAR-α), ATRA is unable to reduce levels of TGF-β–induced phospho-Smad2/3, coincident with its inability to differentiate these cells along granulocytic pathways. Together, these data suggest a new level of cross-talk between ATRA and TGF-β, whereby a putative RAR-α–dependent phosphatase activity limits the levels of phospho-Smad2/3 induced by TGF-β, ultimately reducing the levels of nuclear Smad complexes mediating the TGF-β–dependent differentiation of the cells to monocytic end points.

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Section: Discussionsupporting

confidence: 78%

Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF-β and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells

Cao

Flanders

Bertolette

et al. 2003

Blood

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“…In breast cancer cells, this effect can be abrogated by addition of neutralizing TGF-beta antibodies, which strongly indicates that the growth inhibitory effect of vitamin D on these cells is due, at least in part, to an increased activity of TGF-beta (109,155,156). This observation is consistent with results obtained in leukemia cells, which demonstrated an enhanced expression of TGF-beta receptors in response to treatment of the cells with vitamin D (157). TGF-beta has previously been shown to affect some of the same intracellular targets as vitamin D, including c-myc, pRb, p21 and p27, suggesting that TGF-beta and vitamin D share parts of the same signaling pathways (109,158).…”

Section: Growth Factors and Hormonessupporting

confidence: 86%

Vitamin D and cancer: effects of 1,25(OH)2D3 and its analogs on growth control and tumorigenesis

Hansen

Binderup²,

Hamberg³

et al. 2001

Front Biosci

148

118

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Today, it is well established that besides playing a crucial role in the establishment and maintenance of the calcium homeostasis in the body, the active form of vitamin D, 1,25(OH)2D3, also acts an effective regulator of cell growth and differentiation in a number of different cell types, including cancer cells. This has led to an increased interest in using 1,25(OH)2D3 in the treatment or prevention of cancer patients and to a substantial number of studies investigating the effect of 1,25(OH)2D3 on cancer cells. The results are encouraging, but clearly demonstrate that the therapeutic window of 1,25(OH)2D3 is extremely narrow due to the calcemic adverse effects of this compound. Much effort has consequently been directed into identifying vitamin D analogs with potent cell regulatory effects but with weaker effects on the calcium metabolism than those of 1,25(OH)2D3. In an attempt to clarify the mechanisms implicated in the cell regulatory effects of 1,25(OH)2D3 and eventually facilitate the process of developing new specific vitamin D analogs, numerous investigations have been carried out with 1,25(OH)2D3 and its analogs. The present review will focus on the results obtained in these studies and describe some of the synthetic analogs, which have shown to be of particular interest in relation to cancer.

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“…Signaling pathways induced by 1,25(OH) 2 D 3 and TGF-␤1 have been shown to interact in several noncolonic cell types, resulting in increased TGF-␤1 release (17,23), enhanced TGF-␤ receptor expression (21,50,51), decreased cell growth (17,23), and enhanced differentiation (35). In the present study, although TGF-␤1 alone had no effect on cell growth, the combination of 1,25(OH) 2 D 3 and TGF-␤1 caused significantly more growth inhibition than 1,25(OH) 2 D 3 alone.…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, signaling pathways activated by 1,25(OH) 2 D 3 and TGF-␤ are known to have relevant biological interactions in several noncolonic cell types, including synergistic inhibitory effects on cell growth (17,21,50). The TGF-␤ superfamily, like 1,25(OH) 2 D 3 , regulates a broad range of important cellular processes,includingproliferation,differentiation,andapoptosis (38).…”

mentioning

confidence: 99%

Transforming growth factor-β1 signaling contributes to Caco-2 cell growth inhibition induced by 1,25(OH)₂D₃

Chen

Davis

Sitrin

et al. 2002

American Journal of Physiology-Gastrointestinal and Liver Physi

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Growth of Caco-2 and many cancer cells is inhibited by 1,25(OH)2D3. Whereas TGF-β1 inhibits normal colonic epithelial cell growth, most human colon cancer-derived cells, including Caco-2 and SW480 cells, are resistant to it. The mechanisms underlying these antiproliferative actions and resistance to TGF-β growth inhibition are largely unknown. We observed that 1,25-dihydroxyvitamin D3[1,25(OH)2D3] sensitized Caco-2 and SW480 cells to TGF-β1 growth inhibitory effects. Versus 1,25(OH)2D3 alone, the combination of 1,25(OH)2D3 and TGF-β1 significantly reduced cell numbers. Also, the amount of active TGF-β1 was increased (∼4-fold) by this secosteroid in conditioned media from Caco-2 cells. The 1,25(OH)2D3 increased the expression of IGF-II receptors (IGF-IIR), which facilitated activation of latent TGF-β1, and was found to activate TGF-β signaling in Caco-2 cells. By using neutralizing antibodies to human TGF-β1, we showed that this cytokine contributes to secosteroid-induced inhibition of Caco-2 cell growth. Also, 1,25(OH)2D3 was found to enhance the type I TGF-β receptor mRNA and protein abundance in Caco-2 cells. Whereas the 1,25(OH)2D3-induced sensitization of Caco-2 cells to TGF-β1 was IGF-IIR independent, the type I TGF-β1 receptor was required for this sensitization. Thus 1,25(OH)2D3 treatment of Caco-2 cells results in activation of latent TGF-β1, facilitated by the enhanced expression of IGF-IIR by this secosteroid. Also, 1,25(OH)2D3 sensitized Caco-2 cells to growth inhibitory effects of TGF-β1, contributing to the inhibition of Caco-2 cell growth by this secosteroid.

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Antiproliferative effect of a vitamin D3 analog, EB1089, on HL-60 cells by the induction of TGF-β receptor

Cited by 30 publications

References 34 publications

Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF-β and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells

Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF-β and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells

Vitamin D and cancer: effects of 1,25(OH)2D3 and its analogs on growth control and tumorigenesis

Transforming growth factor-β1 signaling contributes to Caco-2 cell growth inhibition induced by 1,25(OH)₂D₃

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Antiproliferative effect of a vitamin D3 analog, EB1089, on HL-60 cells by the induction of TGF-β receptor

Cited by 30 publications

References 34 publications

Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF-β and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells

Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF-β and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells

Vitamin D and cancer: effects of 1,25(OH)2D3 and its analogs on growth control and tumorigenesis

Transforming growth factor-β1 signaling contributes to Caco-2 cell growth inhibition induced by 1,25(OH)2D3

Contact Info

Product

Resources

About

Transforming growth factor-β1 signaling contributes to Caco-2 cell growth inhibition induced by 1,25(OH)₂D₃