Src family kinase inhibitor bosutinib enhances retinoic acid-induced differentiation of HL-60 leukemia cells

MacDonald, Robert; Bunaciu, Rodica P.; Ip, Victoria; Dai, David L.; Tran, David; Varner, Jeffrey D.; Yen, Andrew

doi:10.1080/10428194.2018.1452213

Cited by 13 publications

(13 citation statements)

References 34 publications

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“…Miranda et al [48] reported that the inhibition of Src family kinases enhances ATRA-induced myeloid cell differentiation. In contrast we reported that putative SFK inhibitors could in fact enhance the signaling that drives differentiation and enhance differentiation [9,40]. It is ergo not clear how SFK activity regulated ATRA-induced differentiation, although the significant engagement of Lyn in the action of ATRA and roscovitine was indicated by our earlier data.…”

Section: Lyn Knockdown Enhances Atra and Roscovitineinduced Nuclear Pmentioning

confidence: 58%

“…We reported that ATRA causes up-regulation of Lyn. However, previous reports show that some SFK inhibitors enhanced the ATRA-induced expression of SFK members, Lyn and Fgr, as well as activated signaling which was associated with promoting cell cycle arrest and differentiation [9,24,40]. And Lyn knock down also did this, too.…”

Section: Discussionmentioning

confidence: 91%

“…The signalsome results in nuclear events that enable RAR/RXR, ATRA activated transcription factors, to transcriptionally activate their target genes to drive differentiation and cell cycle arrest. For example, our laboratory reported that the SFK inhibitors PP2, dasatinib, and bosutinib modulate MAPK signaling and enhance the therapeutic effects of ATRA in various myeloid leukemia cells [9,40]. We have also found that AhR ligands, specifically FICZ and VAF347, used with ATRA enhance induced differentiation [57,58].…”

Section: Discussionmentioning

confidence: 96%

“…SFKs function to promote ATRA-induced differentiation [9,40]. We therefore tested if roscovitine affected them in a way consistent with driving differentiation.…”

Section: Roscovitine Enhances the Atra-induced Expression Of Sfks Andmentioning

confidence: 99%

“…We therefore tested if roscovitine affected them in a way consistent with driving differentiation. Lyn and Fgr are the predominant SFKs in these cells, and they are up-regulated with ATRA treatment [40]. Given that these ATRA-regulated SFKs participate in inducing differentiation, we characterized the effects of co-treatment with ATRA and roscovitine by measuring their expression and activating phosphorylation.…”

Section: Roscovitine Enhances the Atra-induced Expression Of Sfks Andmentioning

confidence: 99%

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Roscovitine enhances all-trans retinoic acid (ATRA)-induced nuclear enrichment of an ensemble of activated signaling molecules and augments ATRA-induced myeloid cell differentiation

et al. 2020

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Although ATRA represents a successful differentiation therapy for APL, it is largely ineffective for non-APL AMLs. Hence combination therapies using an agent targeting ATRA-regulated molecules that drive cell differentiation/arrest are of interest. Using the HL-60 human non-APL AML model where ATRA causes nuclear enrichment of c-Raf that drives differentiation/G0-arrest, we now observe that roscovitine enhanced nuclear enrichment of certain traditionally cytoplasmic signaling molecules and enhanced differentiation and cell cycle arrest. Roscovitine upregulated ATRA-induced nuclear c-Raf phosphorylation at S259 and S289/296/301. Nuclear c-Raf interacted with RB protein and specifically with pS608RB, the hinge region phosphorylation controlling E2F binding and cell cycle progression. ATRA-induced loss of pS608RB with cell cycle arrest was associated with loss of RB-sequestered c-Raf, thereby coupling cell cycle arrest and increased availability of c-Raf to promote differentiation. Part of this mechanism reflects promoting cell cycle arrest via ATRAinduced upregulation of the p27 Kip1 CDKI. Roscovitine also enhanced the ATRAinduced nuclear enrichment of other signaling molecules traditionally perceived as cytoplasmic promoters of proliferation, but now known to promote differentiation; in particular: SFKs, Lyn, Fgr; adaptor proteins, c-Cbl, SLP-76; a guanine exchange factor, Vav1; and a transcription factor, IRF-1. Akin to c-Raf, Lyn bound to RB, specifically to pS608RB. Lyn-pS608RB association was greatly diminished by ATRA and essentially lost in ATRA plus roscovitine treated cells. Interestingly Lyn-KD enhanced such ATRAinduced nuclear signaling and differentiation and made roscovitine more effective. ATRA thus mobilized traditionally cytoplasmic signaling molecules to the nucleus where they drove differentiation which were further enhanced by roscovitine.

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Section: Lyn Knockdown Enhances Atra and Roscovitineinduced Nuclear Pmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 96%

“…SFKs function to promote ATRA-induced differentiation [9,40]. We therefore tested if roscovitine affected them in a way consistent with driving differentiation.…”

Section: Roscovitine Enhances the Atra-induced Expression Of Sfks Andmentioning

confidence: 99%

Section: Roscovitine Enhances the Atra-induced Expression Of Sfks Andmentioning

confidence: 99%

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