Activation of the Aryl Hydrocarbon Receptor AhR Promotes Retinoic Acid–Induced Differentiation of Myeloblastic Leukemia Cells by Restricting Expression of the Stem Cell Transcription Factor Oct4

Bunaciu, Rodica P.; Yen, Andrew

doi:10.1158/0008-5472.can-10-2299

Cited by 76 publications

(95 citation statements)

References 40 publications

(49 reference statements)

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“…Nevertheless, AHR is postulated to play important roles not only in the regulation of xenobiotic metabolism but also in the regulation of differentiation in pro-inflammatory T cells [19], ketarinocytes [20], myeloblastic leukemia cells [21], and Neuro2a cells [22].…”

Section: Introductionmentioning

confidence: 99%

Silencing of miR-124 induces neuroblastoma SK-N-SH cell differentiation, cell cycle arrest and apoptosis through promoting AHR

Huang¹,

Chang²,

Chen³

et al. 2011

FEBS Letters

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a b s t r a c tNeuroblastoma is the most common extracranial solid tumor in children. We investigate whether miR-124, the abundant neuronal miRNA, plays a pivotal role in neuroblastoma. Knockdown of miR-124 promotes neuroblastoma SK-N-SH cell differentiation, cell cycle arrest and apoptosis. Further miR-124 is predicted to target aryl hydrocarbon receptor (AHR) which may promote neuroblastoma cell differentiation. We validate that miR-124 may suppress the expression of AHR by targeting its 3 0 -UTR. These results suggest that miR-124 could serve as a potential therapeutic target of neuroblastoma.

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Section: Introductionmentioning

confidence: 99%

Silencing of miR-124 induces neuroblastoma SK-N-SH cell differentiation, cell cycle arrest and apoptosis through promoting AHR

Huang¹,

Chang²,

Chen³

et al. 2011

FEBS Letters

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“…question is warranted. It has been postulated that the AHR could drive pluripotent cells toward differentiation through its ability to downregulate the stem cell transcription factor Oct4 (Bunaciu and Yen, 2011), which would be a possible mechanism underlying the induction of proliferation and the maintenance of the undifferentiated state of chicken PGCs that we observed after AHR blockade. Besides, it has been demonstrated in an in vitro model of induced gametogenesis that toxicological activation of AHR through PAH exposure promotes the apoptosis of chicken PGCs (Ge et al, 2012).…”

Section: Discussionmentioning

confidence: 69%

Improvement of Chicken Primordial Germ Cell Maintenance In Vitro by Blockade of the Aryl Hydrocarbon Receptor Endogenous Activity

et al. 2016

Cellular Reprogramming

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Primordial germ cells (PGCs) are the undifferentiated progenitors of gametes. Germline competent PGCs can be developed as a cell-based system for genetic modification in chickens, which provides a valuable tool for transgenic technology with both research and industrial applications. This implies manipulation of PGCs, which, in recent years, encouraged a lot of research focused on the study of PGCs and the way of improving their culture. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that besides mediating toxic responses to environmental contaminants plays pivotal physiological roles in various biological processes. Since a novel compound that acts as an antagonist of this receptor has been reported to promote expansion of hematopoietic stem cells, we conducted the present study with the aim of determining whether addition of an established AHR antagonist to the standard culture medium used nowadays for in vitro chicken PGCs culture improves ex vivo expansion. We have found that addition of a-naphthoflavone in culture medium promotes the amplification of undifferentiated cells and that this effect is exerted by the blockade of AHR action. Our results constitute the first report of the successful use of a readily available AHR antagonist to improve avian PGCs expansion, and they further extend the knowledge of the effects of AHR modulation in undifferentiated cells.

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“…PD98059, for example, is a flavonoid that can act as an antagonist of aryl hydrocarbon receptor (AhR) at the same concentrations used to inhibit MEK [43]. AhR has been implicated as a positive regulator of RA-induced HL-60 differentiation [14,34]. Akti-1/2 is a highly selective, noncompetitive Akt inhibitor, but can inhibit the AhR pathway through its off-target inhibition of CAMKIα activity [44,45].…”

Section: Discussionmentioning

confidence: 99%

“…However, inhibiting MEK after RA-induced HL-60 that has completed one division cycle does not inhibit RA-induced differentiation [13], indicating that sustained MEK or ERK activation may be necessary only during the lineage-uncommitted, priming phase and not for the second (lineage commitment) division. c-Raf phosphorylation concurrent with reduced MEK/ERK activation is known [14–18]. …”

Section: Introductionmentioning

confidence: 99%

GW5074 and PP2 kinase inhibitors implicate nontraditional c-Raf and Lyn function as drivers of retinoic acid-induced maturation

Jensen

Bunaciu

Varner

et al. 2015

Cellular Signalling

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The multivariate nature of cancer necessitates multi-targeted therapy, and kinase inhibitors account for a vast majority of approved cancer therapeutics. While acute promyelocytic leukemia (APL) patients are highly responsive to retinoic acid (RA) therapy, kinase inhibitors have been gaining momentum as co-treatments with RA for non-APL acute myeloid leukemia (AML) differentiation therapies, especially as a means to treat relapsed or refractory AML patients. In this study GW5074 (a c-Raf inhibitor) and PP2 (a Src-family kinase inhibitor) enhanced RA-induced maturation of t(15;17)-negative myeloblastic leukemia cells and rescued response in RA-resistant cells. PD98059 (a MEK inhibitor) and Akti-1/2 (an Akt inhibitor) were less effective, but did tend to promote maturation-uncoupled G1/G0 arrest, while wortmannin (a PI3K inhibitor) did not enhance differentiation surface marker expression or growth arrest. PD98059 and Akti-1/2 did not enhance differentiation markers and have potential, antagonistic off-targets effects on the aryl hydrocarbon receptor (AhR), but neither could the AhR agonist 6-formylindolo(3,2-b)carbazole (FICZ) rescue differentiation events in the RA-resistant cells. GW5074 rescued early CD38 expression in RA-resistant cells exhibiting an early block in differentiation before CD38 expression, while for RA-resistant cells with differentiation blocked later, PP2 rescued the later differentiation marker CD11b; but surprisingly, the combination of the two was not synergistic. Kinases c-Raf, Src-family kinases Lyn and Fgr, and PI3K display highly correlated signaling changes during RA treatment, while activation of traditional downstream targets (Akt, MEK/ERK), and even the surface marker CD38, were poorly correlated with c-Raf or Lyn during differentiation. This suggests that an interrelated kinase module involving c-Raf, PI3K, Lyn and perhaps Fgr functions in a nontraditional way during RA-induced maturation or during rescue of RA induction therapy using inhibitor co-treatment in RA-resistant leukemia cells.

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Activation of the Aryl Hydrocarbon Receptor AhR Promotes Retinoic Acid–Induced Differentiation of Myeloblastic Leukemia Cells by Restricting Expression of the Stem Cell Transcription Factor Oct4

Cited by 76 publications

References 40 publications

Silencing of miR-124 induces neuroblastoma SK-N-SH cell differentiation, cell cycle arrest and apoptosis through promoting AHR

Silencing of miR-124 induces neuroblastoma SK-N-SH cell differentiation, cell cycle arrest and apoptosis through promoting AHR

Improvement of Chicken Primordial Germ Cell Maintenance In Vitro by Blockade of the Aryl Hydrocarbon Receptor Endogenous Activity

GW5074 and PP2 kinase inhibitors implicate nontraditional c-Raf and Lyn function as drivers of retinoic acid-induced maturation

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