苯乙双胍通过 NIBAN1 和 DDIT4 激活 ER 应激,促进口腔鳞状细胞癌细胞自噬性死亡,而与 AMPK 无关

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE
Dexuan Zhuang, Shuangshuang Wang, Huiting Deng, Yuxin Shi, Chang Liu, Xue Leng, Qun Zhang, Fuxiang Bai, Bin Zheng, Jing Guo, Xunwei Wu
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引用次数: 0

摘要

口腔鳞状细胞癌(OSCC)的有效临床治疗仍然是一项挑战,需要开发有效的新药。与二甲双胍相比,苯乙双胍对不同肿瘤具有更强的抗肿瘤活性,但苯乙双胍对OSCC细胞的影响却鲜为人知。我们发现苯乙双胍可抑制OSCC细胞增殖,促进OSCC细胞自噬和凋亡,从而显著抑制OSCC细胞在体内和体外的生长。RNA-seq分析显示,自噬通路是苯福明的主要靶点,并发现了两个新靶点DDIT4(DNA损伤诱导转录本4)和NIBAN1(尼班凋亡调节因子1)。我们发现苯福明能明显诱导DDIT4和NIBAN1的表达,从而促进OSCC的自噬。此外,苯乙福明诱导的DDIT4和NIBAN1的表达增强并未被AMPK的敲除所阻断,但却被苯乙福明处理OSCC细胞时诱导的转录因子ATF4(活化转录因子4)的敲除所抑制。这些结果从机理上揭示了苯福明引发内质网(ER)应激激活PERK(蛋白激酶R样ER激酶),PERK使过渡初始因子eIF2磷酸化,eIF2磷酸化增加导致ATF4翻译增加。综上所述,我们发现苯乙双胍能诱导其新靶点DDIT4,尤其是NIBAN1,促进细胞自噬和凋亡,从而抑制OSCC细胞的生长。我们的研究为苯福明在未来治疗 OSCC 的潜在临床应用提供了支持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Phenformin activates ER stress to promote autophagic cell death via NIBAN1 and DDIT4 in oral squamous cell carcinoma independent of AMPK

Phenformin activates ER stress to promote autophagic cell death via NIBAN1 and DDIT4 in oral squamous cell carcinoma independent of AMPK

The efficient clinical treatment of oral squamous cell carcinoma (OSCC) is still a challenge that demands the development of effective new drugs. Phenformin has been shown to produce more potent anti-tumor activities than metformin on different tumors, however, not much is known about the influence of phenformin on OSCC cells. We found that phenformin suppresses OSCC cell proliferation, and promotes OSCC cell autophagy and apoptosis to significantly inhibit OSCC cell growth both in vivo and in vitro. RNA-seq analysis revealed that autophagy pathways were the main targets of phenformin and identified two new targets DDIT4 (DNA damage inducible transcript 4) and NIBAN1 (niban apoptosis regulator 1). We found that phenformin significantly induces the expression of both DDIT4 and NIBAN1 to promote OSCC autophagy. Further, the enhanced expression of DDIT4 and NIBAN1 elicited by phenformin was not blocked by the knockdown of AMPK but was suppressed by the knockdown of transcription factor ATF4 (activation transcription factor 4), which was induced by phenformin treatment in OSCC cells. Mechanistically, these results revealed that phenformin triggers endoplasmic reticulum (ER) stress to activate PERK (protein kinase R-like ER kinase), which phosphorylates the transitional initial factor eIF2, and the increased phosphorylation of eIF2 leads to the increased translation of ATF4. In summary, we discovered that phenformin induces its new targets DDIT4 and especially NIBAN1 to promote autophagic and apoptotic cell death to suppress OSCC cell growth. Our study supports the potential clinical utility of phenformin for OSCC treatment in the future.

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来源期刊
International Journal of Oral Science
International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-
CiteScore
31.80
自引率
1.30%
发文量
53
审稿时长
>12 weeks
期刊介绍: The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.
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