Fangchinoline diminishes STAT3 activation by stimulating oxidative stress and targeting SHP-1 protein in multiple myeloma model
| Autor: | Young Yun Jung, Jae-Young Um, Kwang Seok Ahn, In Jin Ha, Gautam Sethi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Medicine (General) IHC Immunohistochemistry Science (General) FCN Fangchinoline STAT3 signal transducer and activator of transcription 3 Pharmaceutical Science P/S Penicillin-streptomycin Apoptosis Fangchinoline NT Non treat medicine.disease_cause Stat3 Signaling Pathway STAT3 Q1-390 Mice 0302 clinical medicine Multiple myeloma Multidisciplinary SHP-1 Src homology 2 domain-containing protein tyrosine phosphatase-1 biology Chemistry Protein Tyrosine Phosphatase Non-Receptor Type 6 ROS c/w Cell per well VEGF vascular endothelial growth factor Cell biology 030220 oncology & carcinogenesis JAK Janus kinase PARP Poly (ADP-ribose) polymerase DMEM Dulbecco’s Modified Eagle Medium HRP Horseradish peroxidase STAT3 Transcription Factor Programmed cell death MMP Matrix metalloproteinase Benzylisoquinolines 03 medical and health sciences R5-920 RTCA Real-time cell analysis medicine GSH Animals Electrophoretic mobility shift assay ComputingMethodologies_COMPUTERGRAPHICS GAPDH Glyceraldehyde 3-phosphate dehydrogenase Cell growth RT-PCR Reverse transcription polymerase chain reaction ICC Immunocytochemistry Oxidative Stress 030104 developmental biology ip Intraperitoneal injection Tumor progression DAPI 4′ 6-Diamidino-2-Phenylindole Dihydrochloride biology.protein STAT protein FBS Fetal bovine serum Carcinogenesis |
| Zdroj: | Journal of Advanced Research Journal of Advanced Research, Vol 35, Iss, Pp 245-257 (2022) |
| ISSN: | 2090-1224 2090-1232 |
| Popis: | Graphical abstract Highlights • Aberrant STAT3 activation can promote neoplastic transformation by affecting cellular proliferation, invasion, metastasis, angiogenesis, and anti-apoptosis induction. • Fangchinoline abrogated protein expression levels of STAT3 and upstream signals (JAK1/2 and Src) in different tumor cells. • Fangchinoline inhibited the levels of various tumorigenic markers and promoted marked apoptosis through degradation of PARP and caspase-3. • Fangchinoline attenuated the level of STAT3 and upstream signals and suppressed the level of anti- apoptotic proteins in xenograft mice model. Introduction The development of cancer generally occurs as a result of various deregulated molecular mechanisms affecting the genes that can control normal cellular growth. Signal transducer and activator of transcription 3 (STAT3) pathway, once aberrantly activated can promote carcinogenesis by regulating the transcription of a number of oncogenic genes. Objectives Here, we evaluated the impact of fangchinoline (FCN) to attenuate tumor growth and survival through modulation of oncogenic STAT3 signaling pathway using diverse tumor cell lines and a xenograft mouse model. Methods To evaluate the action of FCN on STAT3 cascade, protein levels were analyzed by Western blot analysis and electrophoretic mobility shift assay (EMSA). Translocation of STAT3 was detected by immunocytochemistry. Thereafter, FCN-induced ROS was measured by GSH/GSSG assay and H2DCF-DA. FCN-induced apoptosis was analyzed using Western blot analysis and flow cytometry for various assays. Finally, anti-cancer effects of FCN in vivo was evaluated in a myeloma model. Results We noted that FCN abrogated protein expression levels of STAT3 and upstream signals (JAK1/2 and Src). In addition, FCN also attenuated DNA binding ability of STAT3 and its translocation into the nucleus. It altered the levels of upstream signaling proteins, increased SHP-1 levels, and induced substantial apoptosis in U266 cells. FCN also promoted an increased production of reactive oxygen species (ROS) and altered GSSG/GSH ratio in tumor cells. Moreover, FCN effectively abrogated tumor progression and STAT3 activation in a preclinical myeloma model. Conclusion Overall, this study suggests that FCN may have a tremendous potential to alter abnormal STAT3 activation and induce cell death in malignant cells along with causing the suppression of pathogenesis and growth of cancer through a pro-oxidant dependent molecular mechanism. |
| Databáze: | OpenAIRE |
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