Oncotarget

Research Papers:

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

Harrison T. Supnick, Rodica P. Bunaciu and Andrew Yen _

PDF  |  HTML  |  How to cite

Oncotarget. 2018; 9:9808-9824. https://doi.org/10.18632/oncotarget.24275

Metrics: PDF 1123 views  |   HTML 2190 views  |   ?  


Abstract

Harrison T. Supnick2, Rodica P. Bunaciu1 and Andrew Yen1

1Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA

2University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA

Correspondence to:

Andrew Yen, email: [email protected]

Keywords: RRD-251; myeloid; HL-60; MAPK; GSK-3

Received: November 17, 2017     Accepted: January 09, 2018     Published: January 19, 2018

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 24275