The Chemopreventive Phytochemical Moringin Isolated from Moringa oleifera Seeds Inhibits JAK/STAT Signaling.
Sulforaphane (SFN) and moringin (GMG-ITC) are edible isothiocyanates present as glucosinolate precursors in cruciferous vegetables and in the plant Moringa oleifera respectively, and recognized for their chemopreventive and medicinal properties. In contrast to the well-studied SFN, little is known about the molecular pathways targeted by GMG-ITC. We investigated the ability of GMG-ITC to inhibit essential signaling pathways that are frequently upregulated in cancer and immune disorders, such as JAK/STAT and NF-κB. We report for the first time that, similarly to SFN, GMG-ITC in the nanomolar range suppresses IL-3-induced expression of STAT5 target genes. GMG-ITC, like SFN, does not inhibit STAT5 phosphorylation, suggesting a downstream inhibitory event. Interestingly, treatment with GMG-ITC or SFN had a limited inhibitory effect on IFNα-induced STAT1 and STAT2 activity, indicating that both isothiocyanates differentially target JAK/STAT signaling pathways. Furthermore, we showed that GMG-ITC in the micromolar range is a more potent inhibitor of TNF-induced NF-κB activity than SFN. Finally, using a cellular system mimicking constitutive active STAT5-induced cell transformation, we demonstrated that SFN can reverse the survival and growth advantage mediated by oncogenic STAT5 and triggers cell death, therefore providing experimental evidence of a cancer chemopreventive activity of SFN. This work thus identified STAT5, and to a lesser extent STAT1/STAT2, as novel targets of moringin. It also contributes to a better understanding of the biological activities of the dietary isothiocyanates GMG-ITC and SFN and further supports their apparent beneficial role in the prevention of chronic illnesses such as cancer, inflammatory diseases and immune disorders.
Stat5 Signaling Research Group, Institute of Immunology, University of Regensburg, Regensburg, Germany.
Carina
C
Michl
Stat5 Signaling Research Group, Institute of Immunology, University of Regensburg, Regensburg, Germany.|Molecular toxicology unit, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Fabio
F
Vivarelli
Stat5 Signaling Research Group, Institute of Immunology, University of Regensburg, Regensburg, Germany.
Julia
J
Weigl
Consiglio per la ricerca in agricoltura e l'analisi dell'economia agraria, Centro di ricerca per le colture industriali (CREA-CIN), Bologna, Italy.
Gina Rosalinda
GR
De Nicola
Molecular toxicology unit, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Donatella
D
Canistro
Molecular toxicology unit, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Moreno
M
Paolini
Consiglio per la ricerca in agricoltura e l'analisi dell'economia agraria, Centro di ricerca per le colture industriali (CREA-CIN), Bologna, Italy.
Renato
R
Iori
Stat5 Signaling Research Group, Institute of Immunology, University of Regensburg, Regensburg, Germany.
Anne
A
Rascle
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D017879:Isothiocyanates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D029588:Moringa oleifera / Q000737:chemistry*; D010766:Phosphorylation / Q000187:drug effects; D054448:Precursor Cells, B-Lymphoid / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012639:Seeds / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
D016898:Interferon-alpha; D007377:Interleukin-3; D017879:Isothiocyanates; D050791:STAT Transcription Factors; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050799:STAT5 Transcription Factor; C000614007:moringin; D053612:Janus Kinases