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Molecular Cancer
Published in: Molecular Cancer 1/2013

Open Access 01-12-2013 | Research

6-Formylindolo (3,2-b)carbazole (FICZ) enhances retinoic acid (RA)-induced differentiation of HL-60 myeloblastic leukemia cells

Authors: Rodica P Bunaciu, Andrew Yen

Published in: Molecular Cancer | Issue 1/2013

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Abstract

Background

The aryl hydrocarbon receptor (AhR) ligand 6-Formylindolo(3,2-b)carbazole (FICZ) has received increasing attention since its identification as an endogenous AhR ligand and a photoproduct of tryptophan. FICZ and its metabolites have been detected in human fluids. We recently reported that AhR promotes retinoic acid (RA)-induced granulocytic differentiation of HL-60 myeloblastic leukemia cells by restricting the nuclear abundance of the stem cell associated transcription factor Oct4. The standard clinical management of acute promyelocytic leukemia (APL) is differentiation induction therapy using RA. But RA is not effective for other myeloid leukemias, making the mechanism of RA-induced differentiation observed in a non-APL myeloid leukemia of interest. To our knowledge, this is the first study regarding the influence of FICZ on RA-induced differentiation in any type of leukemic blasts.

Methods

Using flow cytometry and Western blotting assays, we determined the effects of FICZ on RA-induced differentiation of HL-60 human leukemia cells. All experiments were performed in triplicate. The groups RA and FICZ + RA were compared using the Paired-Samples T-Test. Western blot figures present the typical blots.

Results

We demonstrate that FICZ enhances RA-induced differentiation, assessed by the expression of the membrane differentiation marker CD11b; cell cycle arrest; and the functional differentiation marker, inducible-oxidative metabolism. FICZ causes changes in signaling events that are known to drive differentiation, and notably augments the RA-induced sustained activation of the RAF/MEK/ERK axis of the mitogen-activated protein kinase (MAPK) cascade. FICZ also augments expression of the known MAPK signaling regulatory molecules c-Cbl, VAV1, pY458 p85 PI3K, Src-family kinases (SFKs), and IRF-1, a transcription factor associated with this putative signalsome that promotes RA-induced differentiation. Moreover, FICZ in combination with RA also increases expression of AhR and even more so of both Cyp1A2 and p47phox, which are known to be transcriptionally regulated by AhR. pY1021 PDGFRβ, a marker associated with retinoic acid syndrome was also increased.

Conclusions

Our data suggest that FICZ modulates intracellular signaling pathways and enhances RA-induced differentiation.
Appendix
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Literature
1.
Bunaciu RP, Yen A: 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. Cancer Res. 2011, 71: 2371-2380. 10.1158/0008-5472.CAN-10-2299PubMedCentralCrossRefPubMed
2.
Harper PA, Giannone JV, Okey AB, Denison MS: In vitro transformation of the human Ah receptor and its binding to a dioxin response element. Mol Pharmacol. 1992, 42: 603-612.PubMed
3.
Ohtake F, Baba A, Takada I, Okada M, Iwasaki K, Miki H, Takahashi S, Kouzmenko A, Nohara K, Chiba T: Dioxin receptor is a ligand-dependent E3 ubiquitin ligase. Nature. 2007, 446: 562-566. 10.1038/nature05683CrossRefPubMed
4.
Ma Q: Induction of CYP1A1. The AhR/DRE paradigm: transcription, receptor regulation, and expanding biological roles. Curr Drug Metab. 2001, 2: 149-164. 10.2174/1389200013338603CrossRefPubMed
5.
Soprano DR, Soprano KJ: Pharmacological doses of some synthetic retinoids can modulate both the aryl hydrocarbon receptor and retinoid receptor pathways. J Nutr. 2003, 133: 277S-281S.PubMed
6.
Shenefelt RE: Gross congenital malformations. Animal model: treatment of various species with a large dose of vitamin a at known stages in pregnancy. Am J Pathol. 1972, 66: 589-592.PubMedCentralPubMed
7.
Mimura J, Yamashita K, Nakamura K, Morita M, Takagi TN, Nakao K, Ema M, Sogawa K, Yasuda M, Katsuki M, Fujii-Kuriyama Y: Loss of teratogenic response to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor. Genes Cells. 1997, 2: 645-654.CrossRefPubMed
8.
Hayashida Y, Kawamura T, Hori-e R, Yamashita I: Retionic acid and its receptors are required for expression of aryl hydrocarbon receptor mRNA and embryonic development of blood vessel and bone in the medaka fish, Oryzias latipes. Zoolog Sci. 2004, 21: 541-551. 10.2108/zsj.21.541CrossRefPubMed
9.
Hall JM, Barhoover MA, Kazmin D, McDonnell DP, Greenlee WF, Thomas RS: Activation of the aryl-hydrocarbon receptor inhibits invasive and metastatic features of human breast cancer cells and promotes breast cancer cell differentiation. Mol Endocrinol. 2010, 24: 359-369. 10.1210/me.2009-0346PubMedCentralCrossRefPubMed
10.
Fan Y, Boivin GP, Knudsen ES, Nebert DW, Xia Y, Puga A: The aryl hydrocarbon receptor functions as a tumor suppressor of liver carcinogenesis. Cancer Res. 2010, 70: 212-220. 10.1158/0008-5472.CAN-09-3090PubMedCentralCrossRefPubMed
11.
Ikuta T, Kobayashi Y, Kitazawa M, Shiizaki K, Itano N, Noda T, Pettersson S, Poellinger L, Fujii-Kuriyama Y, Taniguchi S, Kawajiri K: ASC-associated inflammation promotes cecal tumorigenesis in aryl hydrocarbon receptor-deficient mice. Carcinogenesis. 2013, 10.1093/carcin/bgt083.
12.
Boitano AE, Wang J, Romeo R, Bouchez LC, Parker AE, Sutton SE, Walker JR, Flaveny CA, Perdew GH, Denison MS: Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science. 2010, 329: 1345-1348. 10.1126/science.1191536PubMedCentralCrossRefPubMed
13.
Bock KW: The human Ah receptor: hints from dioxin toxicities to deregulated target genes and physiologic functions. Biol Chem. 2013, 394: 729-739.CrossRefPubMed
14.
Takahashi K, Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006, 126: 663-676. 10.1016/j.cell.2006.07.024CrossRefPubMed
15.
Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Scholer H, Smith A: Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell. 1998, 95: 379-391. 10.1016/S0092-8674(00)81769-9CrossRefPubMed
16.
Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R: Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007, 318: 1917-1920. 10.1126/science.1151526CrossRefPubMed
17.
Yen A, Roberson MS, Varvayanis S, Lee AT: Retinoic acid induced mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase-dependent MAP kinase activation needed to elicit HL-60 cell differentiation and growth arrest. Cancer Res. 1998, 58: 3163-3172.PubMed
18.
Congleton J, MacDonald R, Yen A: Src inhibitors, PP2 and dasatinib, increase retinoic acid-induced association of Lyn and c-Raf (S259) and enhance MAPK-dependent differentiation of myeloid leukemia cells. Leukemia. 2012, 26: 1180-1188. 10.1038/leu.2011.390PubMedCentralCrossRefPubMed
19.
Shen M, Yen A: c-Cbl interacts with CD38 and promotes retinoic acid-induced differentiation and G0 arrest of human myeloblastic leukemia cells. Cancer Res. 2008, 68: 8761-8769. 10.1158/0008-5472.CAN-08-1058CrossRefPubMed
20.
Yen A, Varvayanis S, Smith JL, Lamkin TJ: Retinoic acid induces expression of SLP-76: expression with c-FMS enhances ERK activation and retinoic acid-induced differentiation/G0 arrest of HL-60 cells. Eur J Cell Biol. 2006, 85: 117-132. 10.1016/j.ejcb.2005.09.020CrossRefPubMed
21.
Shen M, Bunaciu RP, Congleton J, Jensen HA, Sayam LG, Varner JD, Yen A: Interferon regulatory factor-1 binds c-Cbl, enhances mitogen activated protein kinase signaling and promotes retinoic acid-induced differentiation of HL-60 human myelo-monoblastic leukemia cells. Leuk Lymphoma. 2011, 52: 2372-2379. 10.3109/10428194.2011.603449PubMedCentralCrossRefPubMed
22.
Marchisio M, Bertagnolo V, Colamussi ML, Capitani S, Neri LM: Phosphatidylinositol 3-kinase in HL-60 nuclei is bound to the nuclear matrix and increases during granulocytic differentiation. Biochem Biophys Res Commun. 1998, 253: 346-351. 10.1006/bbrc.1998.9787CrossRefPubMed
23.
Bertagnolo V, Grassilli S, Bavelloni A, Brugnoli F, Piazzi M, Candiano G, Petretto A, Benedusi M, Capitani S: Vav1 modulates protein expression during ATRA-induced maturation of APL-derived promyelocytes: a proteomic-based analysis. J Proteome Res. 2008, 7: 3729-3736. 10.1021/pr7008719CrossRefPubMed
24.
Pinel-Marie ML, Sparfel L, Desmots S, Fardel O: Aryl hydrocarbon receptor-dependent induction of the NADPH oxidase subunit NCF1/p47 phox expression leading to priming of human macrophage oxidative burst. Free Radic Biol Med. 2009, 47: 825-834. 10.1016/j.freeradbiomed.2009.06.025CrossRefPubMed
25.
Korn T: How T cells take developmental decisions by using the aryl hydrocarbon receptor to sense the environment. Proc Natl Acad Sci USA. 2010, 107: 20597-20598. 10.1073/pnas.1015420107PubMedCentralCrossRefPubMed
26.
Yen A, Roberson MS, Varvayanis S: Retinoic acid selectively activates the ERK2 but not JNK/SAPK or p38 MAP kinases when inducing myeloid differentiation. In Vitro Cell Dev Biol Anim. 1999, 35: 527-532. 10.1007/s11626-999-0063-zCrossRefPubMed
27.
Wang J, Yen A: A MAPK-positive feedback mechanism for BLR1 signaling propels retinoic acid-triggered differentiation and cell cycle arrest. J Biol Chem. 2008, 283: 4375-4386.CrossRefPubMed
28.
Dougherty MK, Muller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD, Conrads TP, Veenstra TD, Lu KP, Morrison DK: Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell. 2005, 17: 215-224. 10.1016/j.molcel.2004.11.055CrossRefPubMed
29.
Hekman M, Fischer A, Wennogle LP, Wang YK, Campbell SL, Rapp UR: Novel C-Raf phosphorylation sites: serine 296 and 301 participate in Raf regulation. FEBS Lett. 2005, 579: 464-468. 10.1016/j.febslet.2004.11.105CrossRefPubMed
30.
31.
Reiterer G, Bunaciu RP, Smith JL, Yen A: Inhibiting the platelet derived growth factor receptor increases signs of retinoic acid syndrome in myeloid differentiated HL-60 cells. FEBS Lett. 2008, 582: 2508-2514. 10.1016/j.febslet.2008.06.016PubMedCentralCrossRefPubMed
32.
Shen M, Yen A: c-Cbl tyrosine kinase-binding domain mutant G306E abolishes the interaction of c-Cbl with CD38 and fails to promote retinoic acid-induced cell differentiation and G0 arrest. J Biol Chem. 2009, 284: 25664-25677. 10.1074/jbc.M109.014241PubMedCentralCrossRefPubMed
33.
Katagiri K, Yokoyama KK, Yamamoto T, Omura S, Irie S, Katagiri T: Lyn and Fgr protein-tyrosine kinases prevent apoptosis during retinoic acid-induced granulocytic differentiation of HL-60 cells. J Biol Chem. 1996, 271: 11557-11562. 10.1074/jbc.271.19.11557CrossRefPubMed
34.
Donella-Deana A, Cesaro L, Ruzzene M, Brunati AM, Marin O, Pinna LA: Spontaneous autophosphorylation of Lyn tyrosine kinase at both its activation segment and C-terminal tail confers altered substrate specificity. Biochemistry. 1998, 37: 1438-1446. 10.1021/bi971332sCrossRefPubMed
35.
Reiterer G, Yen A: Platelet-derived growth factor receptor regulates myeloid and monocytic differentiation of HL-60 cells. Cancer Res. 2007, 67: 7765-7772. 10.1158/0008-5472.CAN-07-0014CrossRefPubMed
36.
Rinsky RA, Hornung RW, Silver SR, Tseng CY: Benzene exposure and hematopoietic mortality: A long-term epidemiologic risk assessment. Am J Ind Med. 2002, 42: 474-480. 10.1002/ajim.10138CrossRefPubMed
37.
Widerak M, Ghoneim C, Dumontier MF, Quesne M, Corvol MT, Savouret JF: The aryl hydrocarbon receptor activates the retinoic acid receptoralpha through SMRT antagonism. Biochimie. 2006, 88: 387-397. 10.1016/j.biochi.2005.11.007CrossRefPubMed
38.
Kumar MB, Perdew GH: Nuclear receptor coactivator SRC-1 interacts with the Q-rich subdomain of the AhR and modulates its transactivation potential. Gene Expr. 1999, 8: 273-286.PubMed
39.
Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, Lin SC, Heyman RA, Rose DW, Glass CK, Rosenfeld MG: A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell. 1996, 85: 403-414. 10.1016/S0092-8674(00)81118-6CrossRefPubMed
40.
Yang-Yen HF, Zhang XK, Graupner G, Tzukerman M, Sakamoto B, Karin M, Pfahl M: Antagonism between retinoic acid receptors and AP-1: implications for tumor promotion and inflammation. New Biol. 1991, 3: 1206-1219.PubMed
41.
Suh J, Jeon YJ, Kim HM, Kang JS, Kaminski NE, Yang KH: Aryl hydrocarbon receptor-dependent inhibition of AP-1 activity by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin in activated B cells. Toxicol Appl Pharmacol. 2002, 181: 116-123. 10.1006/taap.2002.9403CrossRefPubMed
42.
Klinge CM, Kaur K, Swanson HI: The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRalpha1. Arch Biochem Biophys. 2000, 373: 163-174. 10.1006/abbi.1999.1552CrossRefPubMed
43.
Tran P, Zhang XK, Salbert G, Hermann T, Lehmann JM, Pfahl M: COUP orphan receptors are negative regulators of retinoic acid response pathways. Mol Cell Biol. 1992, 12: 4666-4676.PubMedCentralCrossRefPubMed
44.
Sassano A, Altman JK, Gordon LI, Platanias LC: Statin-dependent activation of protein kinase Cdelta in acute promyelocytic leukemia cells and induction of leukemic cell differentiation. Leuk Lymphoma. 2012, 53: 1779-1784. 10.3109/10428194.2012.668287PubMedCentralCrossRefPubMed
45.
Kambhampati S, Li Y, Verma A, Sassano A, Majchrzak B, Deb DK, Parmar S, Giafis N, Kalvakolanu DV, Rahman A: Activation of protein kinase C delta by all-trans-retinoic acid. J Biol Chem. 2003, 278: 32544-32551. 10.1074/jbc.M301523200CrossRefPubMed
46.
Yen A, Varvayanis S: Retinoic acid increases amount of phosphorylated RAF; ectopic expression of cFMS reveals that retinoic acid-induced differentiation is more strongly dependent on ERK2 signaling than induced GO arrest is. In Vitro Cell Dev Biol Anim. 2000, 36: 249-255. 10.1290/1071-2690(2000)036<0249:RAIAOP>2.0.CO;2CrossRefPubMed
47.
Hoyos B, Jiang S, Hammerling U: Location and functional significance of retinol-binding sites on the serine/threonine kinase, c-Raf. J Biol Chem. 2005, 280: 6872-6878. 10.1074/jbc.M412695200CrossRefPubMed
48.
Hoyos B, Imam A, Korichneva I, Levi E, Chua R, Hammerling U: Activation of c-Raf kinase by ultraviolet light. Regulation by retinoids. J Biol Chem. 2002, 277: 23949-23957. 10.1074/jbc.M110750200CrossRefPubMed
49.
Mukai R, Shirai Y, Saito N, Fukuda I, Nishiumi S, Yoshida K, Ashida H: Suppression mechanisms of flavonoids on aryl hydrocarbon receptor-mediated signal transduction. Arch Biochem Biophys. 2010, 501: 134-141. 10.1016/j.abb.2010.05.002CrossRefPubMed
50.
Enan E, Matsumura F: Identification of c-Src as the integral component of the cytosolic Ah receptor complex, transducing the signal of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) through the protein phosphorylation pathway. Biochem Pharmacol. 1996, 52: 1599-1612. 10.1016/S0006-2952(96)00566-7CrossRefPubMed
51.
Kauss MA, Reiterer G, Bunaciu RP, Yen A: Human myeloblastic leukemia cells (HL-60) express a membrane receptor for estrogen that signals and modulates retinoic acid-induced cell differentiation. Exp Cell Res. 2008, 314: 2999-3006. 10.1016/j.yexcr.2008.07.015PubMedCentralCrossRefPubMed
52.
Brooks SC, Kazmer S, Levin AA, Yen A: Myeloid differentiation and retinoblastoma phosphorylation changes in HL-60 cells induced by retinoic acid receptor- and retinoid X receptor-selective retinoic acid analogs. Blood. 1996, 87: 227-237.PubMed
Metadata
Title
6-Formylindolo (3,2-b)carbazole (FICZ) enhances retinoic acid (RA)-induced differentiation of HL-60 myeloblastic leukemia cells
Authors
Rodica P Bunaciu
Andrew Yen
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2013
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-12-39

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