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c-Raf调节剂RRD-251增强核c-Raf/GSK-3/VDR轴信号传导，并增强1,25-二羟基维生素D3诱导的HL-60髓性白血病细胞分化。

The c-Raf modulator RRD-251 enhances nuclear c-Raf/GSK-3/VDR axis signaling and augments 1,25-dihydroxyvitamin D3-induced differentiation of HL-60 myeloblastic leukemia cells.

作者信息

Supnick Harrison T, Bunaciu Rodica P, Yen Andrew

机构信息

University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.

Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.

出版信息

Oncotarget. 2018 Jan 19;9(11):9808-9824. doi: 10.18632/oncotarget.24275. eCollection 2018 Feb 9.

DOI:10.18632/oncotarget.24275
PMID:29515772
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5839403/
Abstract

Differentiation therapy is used in cancer treatment. Epidemiologic studies showed that higher vitamin D levels are associated with reduced cancer risks. However, the therapeutic doses needed for differentiation are accompanied by hypercalcemia and intolerable pathological sequelae. In the present work we evaluated if RRD-251, a small-molecule, can enhance vitamin D3-induced differentiation of leukemic cells, in the hope of decreasing the needed vitamin D3-dose. We demonstrate that RRD-251 enhances vitamin D3-induced differentiation of leukemic cells, the enrichment of the c-Raf kinase in the nucleus, the binding of nuclear c-Raf to GSK-3, increased phosphorylation of GSK-3 ser 21/9 inhibitory sites, and the binding of GSK-3 to VDR, where GSK-3 inhibition is known to enhance transcriptional activation by VDR. Enhancement of D3-induced p-GSK-3 ser 21/9 by RRD-251 was associated with enhanced Akt-GSK-3 binding, Akt being a known GSK-3 inhibitor, and diminished Erk1/2 binding. Diminishing Erk interaction with GSK-3 was associated with enhanced interaction with Vav1, a known driver of myeloid differentiation. This is redolent of an ATRA/c-Raf/GSK-3/RARα axis we previously reported, although the phosphorylation effects to enhance transcriptional activation on RARα vs VDR diverge. Taken together this indicates potential therapeutic significance for a c-Raf/GSK-3/VDR or RARα axis for leukemic myelo-monocytic differentiation.

摘要

分化疗法用于癌症治疗。流行病学研究表明，较高的维生素D水平与降低癌症风险相关。然而，分化所需的治疗剂量会伴有高钙血症和难以耐受的病理后遗症。在本研究中，我们评估了小分子RRD-251是否能增强维生素D3诱导的白血病细胞分化，以期降低所需的维生素D3剂量。我们证明，RRD-251增强了维生素D3诱导的白血病细胞分化、c-Raf激酶在细胞核中的富集、细胞核c-Raf与GSK-3的结合、GSK-3丝氨酸21/9抑制位点磷酸化增加，以及GSK-3与VDR的结合，已知GSK-3抑制可增强VDR的转录激活。RRD-251增强D3诱导的GSK-3丝氨酸21/9磷酸化与增强Akt-GSK-3结合有关，Akt是一种已知的GSK-3抑制剂，同时减少了Erk1/2结合。减少Erk与GSK-3的相互作用与增强与Vav1的相互作用有关，Vav1是髓系分化的已知驱动因子。这让人联想到我们之前报道的一条ATRA/c-Raf/GSK-3/RARα轴，尽管增强RARα与VDR转录激活的磷酸化效应有所不同。综上所述，这表明c-Raf/GSK-3/VDR或RARα轴在白血病髓单核细胞分化方面具有潜在的治疗意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/80017eb80e91/oncotarget-09-9808-g012.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/da4b1fc1467a/oncotarget-09-9808-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/024fe63aa754/oncotarget-09-9808-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/ff2a7f9e2225/oncotarget-09-9808-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/2f128362abbc/oncotarget-09-9808-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/2e9be9aaa55a/oncotarget-09-9808-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/2b1411b857e2/oncotarget-09-9808-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/688e823a98ab/oncotarget-09-9808-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/80017eb80e91/oncotarget-09-9808-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/9210b4ca9b01/oncotarget-09-9808-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/679971cfffcf/oncotarget-09-9808-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/0401c9652639/oncotarget-09-9808-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/d023506b8940/oncotarget-09-9808-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/da4b1fc1467a/oncotarget-09-9808-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/024fe63aa754/oncotarget-09-9808-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/ff2a7f9e2225/oncotarget-09-9808-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/2f128362abbc/oncotarget-09-9808-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/2e9be9aaa55a/oncotarget-09-9808-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/2b1411b857e2/oncotarget-09-9808-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/688e823a98ab/oncotarget-09-9808-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aca7/5839403/80017eb80e91/oncotarget-09-9808-g012.jpg

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