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Fraxetin inhibits the growth of colon adenocarcinoma cells via the Janus kinase 2/signal transducer and activator of transcription 3 signalling pathway.
Ren, Shuo; Xing, Yanwei; Wang, Chengbo; Jiang, Fengqi; Liu, Guangyu; Li, Ziyi; Jiang, Tao; Zhu, Yuekun; Piao, Daxun.
Afiliación
  • Ren S; Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China.
  • Xing Y; Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China.
  • Wang C; Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China.
  • Jiang F; Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China.
  • Liu G; Department of Anorectal Surgery, The Shenzhen Hospital of Southern Medical University, Southern Medical University, Shenzhen, China.
  • Li Z; The Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China.
  • Jiang T; Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China.
  • Zhu Y; Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China.
  • Piao D; Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China. Electronic address: piaodaxun@sina.com.
Int J Biochem Cell Biol ; 125: 105777, 2020 08.
Article en En | MEDLINE | ID: mdl-32504672
ABSTRACT

OBJECTIVE:

Fraxetin, extracted from the bark of Fraxinus rhynchophylla, has been shown to exhibit antitumour and anti-inflammatory pharmacological properties. However, the mechanism underlying its anticancer activity towards colon adenocarcinoma (COAD) is not well understood. We aimed to determine the antitumour effect of fraxetin on COAD cell lines and elucidate its biochemical and molecular targets.

METHODS:

The cell lines HCT116 and DLD-1 were used to evaluate the in vitro antitumour efficacy of fraxetin. Cytotoxicity and viability were assessed by CCK-8 and plate colony formation assays. Flow cytometry was used to assess apoptosis and cell cycle progression in fraxetin-treated COAD cells. Western blot, RT-qPCR, molecular docking, immunohistochemical, and immunofluorescence analyses were used to gain insights into cellular and molecular mechanisms. Preclinical curative effects were evaluated in nude mouse xenograft models.

RESULTS:

Fraxetin significantly inhibited COAD cell proliferation in both dose- and time-dependent manners, specifically by inducing S-phase cell cycle arrest and triggering intrinsic apoptosis. Additionally, the level of p-JAK2 was decreased by fraxetin via the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signalling pathway. Interestingly, in COAD cells, fraxetin directly targeted the Y1007 and Y1008 residues of JAK2 to suppress its auto- or transphosphorylation, leading to decreased activation of its downstream effector STAT3 and blocking its nuclear translocation. Finally, fraxetin exhibited good tumour growth suppression activity and low toxicity.

CONCLUSIONS:

Fraxetin inhibits the proliferation of COAD cells by regulating the JAK2/STAT3 signalling pathway, providing evidence that targeting JAK2 with fraxetin may offer a novel potential auxiliary therapy for COAD treatment.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Contexto en salud: 6_ODS3_enfermedades_notrasmisibles Problema de salud: 6_chronic_obstructive_pulmonary_disease / 6_colon_rectum_cancers Asunto principal: Adenocarcinoma / Transducción de Señal / Neoplasias del Colon / Cumarinas / Factor de Transcripción STAT3 / Janus Quinasa 2 / Antineoplásicos Fitogénicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Int J Biochem Cell Biol Asunto de la revista: BIOQUIMICA Año: 2020 Tipo del documento: Article País de afiliación: China

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Contexto en salud: 6_ODS3_enfermedades_notrasmisibles Problema de salud: 6_chronic_obstructive_pulmonary_disease / 6_colon_rectum_cancers Asunto principal: Adenocarcinoma / Transducción de Señal / Neoplasias del Colon / Cumarinas / Factor de Transcripción STAT3 / Janus Quinasa 2 / Antineoplásicos Fitogénicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Int J Biochem Cell Biol Asunto de la revista: BIOQUIMICA Año: 2020 Tipo del documento: Article País de afiliación: China
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