TMP: A dual modulator of apoptosis and autophagy via SHP-1 regulation in hepatocellular carcinoma.

IF 5.2 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Life sciences Pub Date : 2024-12-13 DOI:10.1016/j.lfs.2024.123316
Young Yun Jung, Yejin Hong, Dongwoo Nam, Amudha Deivasigamani, Acharan S Narula, Arunachalam Chinnathambi, Ojas A Namjoshi, Bruce E Blough, Sulaiman Ali Alharbi, Kam Man Hui, Gautam Sethi, Kwang Seok Ahn
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Abstract

Background: Hepatocellular carcinoma (HCC) poses a significant health burden due to its high incidence, and current treatment effectiveness is hindered by drug resistance. Thus, investigation of novel therapeutic approaches derived from natural sources is crucial for improving patient outcomes.

Aims: This study aimed to explore the potential of Tetramethylpyrazine (TMP), bioactive alkaloid (ligustrazine) isolated from Chuanxiong (Ligusticum Wallichii), in targeting HCC by inducing apoptosis and enhancing autophagy. The study focused on elucidating the molecular mechanisms underlying anti-cancer effects of TMP.

Main methods: To determine the influence of TMP on apoptosis and autophagy, Western blot analysis, annexin V assay, cell cycle analysis, acridine orange staining, and immunocytochemistry were performed. Next, the activation of the STAT3 signaling pathway and the anti-cancer effects of TMP in vivo were examined in an orthotopic HCCLM3-Lu mouse model.

Key findings: TMP treatment induced apoptosis in HCCLM3 and Hep3B cells by activating key apoptotic factors while inhibiting proteins associated with cell survival and angiogenesis. Additionally, TMP enhanced autophagy by promoting the formation of autophagosomes and stimulating autophagy-related proteins. Furthermore, TMP suppressed the activation of the STAT3 signaling pathway by upregulating SHP-1, thereby inhibiting tumorigenesis and activating cell death pathways. Additionally, our in vivo research demonstrated that TMP significantly inhibited tumor growth and triggered the activation of both apoptosis and autophagy in tumor tissues.

Significance: Our findings of this study demonstrate that TMP exerts a dual-action mechanism by modulating both apoptosis and autophagy, thus offering a promising strategy to overcome drug resistance in HCC.

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背景:肝细胞癌(HCC)发病率高,对健康造成了巨大负担,目前的治疗效果因耐药性而受到阻碍。目的:本研究旨在探索从川芎中分离出的生物活性生物碱(川芎嗪)--四甲基吡嗪(TMP)--通过诱导细胞凋亡和增强自噬作用靶向治疗 HCC 的潜力。研究的重点是阐明TMP抗癌作用的分子机制:为了确定TMP对细胞凋亡和自噬的影响,研究人员进行了Western印迹分析、附件素V检测、细胞周期分析、吖啶橙染色和免疫细胞化学分析。接着,在HCCLM3-Lu小鼠模型中检测了STAT3信号通路的激活情况以及TMP在体内的抗癌作用:主要发现:TMP通过激活关键的凋亡因子诱导HCCLM3和Hep3B细胞凋亡,同时抑制与细胞存活和血管生成相关的蛋白。此外,TMP 还能促进自噬体的形成并刺激自噬相关蛋白,从而增强自噬作用。此外,TMP 还能通过上调 SHP-1 抑制 STAT3 信号通路的激活,从而抑制肿瘤发生并激活细胞死亡通路。此外,我们的体内研究表明,TMP 能显著抑制肿瘤的生长,并引发肿瘤组织中细胞凋亡和自噬的激活:我们的研究结果表明,TMP 可通过调节细胞凋亡和自噬发挥双重作用,从而为克服 HCC 的耐药性提供了一种有前景的策略。
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来源期刊
Life sciences
Life sciences 医学-药学
CiteScore
12.20
自引率
1.60%
发文量
841
审稿时长
6 months
期刊介绍: Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.
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