GCN2-SLC7A11 axis coordinates autophagy, cell cycle and apoptosis and regulates cell growth in retinoblastoma upon arginine deprivation.

IF 6 3区 医学 Q1 CELL BIOLOGY
Dan Wang, Wai Kit Chu, Jason Cheuk Sing Yam, Chi Pui Pang, Yun Chung Leung, Alisa Sau Wun Shum, Sun-On Chan
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引用次数: 0

Abstract

Background: Arginine deprivation was previously shown to inhibit retinoblastoma cell proliferation and induce cell death in vitro. However, the mechanisms by which retinoblastoma cells respond to arginine deprivation remain to be elucidated.

Methods: The human-derived retinoblastoma cell lines Y79 and WERI-Rb-1 were subjected to arginine depletion, and the effects on inhibiting cell growth and survival were evaluated. This study investigated potential mechanisms, including autophagy, cell cycle arrest and apoptosis. Moreover, the roles of the general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1) signaling pathways in these processes were examined.

Results: We demonstrated that arginine deprivation effectively inhibited the growth of retinoblastoma cells in vitro. This treatment caused an increase in the autophagic response. Additionally, prolonged arginine deprivation induced G2 cell cycle arrest and was accompanied by an increase in early apoptotic cells. Importantly, arginine depletion also induced the activation of GCN2 and the inhibition of mTOR signaling. We also discovered that the activation of SLC7A11 was regulated by GCN2 upon arginine deprivation. Knockdown of SLC7A11 rendered retinoblastoma cells partially resistant to arginine deprivation. Furthermore, we found that knockdown of GCN2 led to a decrease in the autophagic response in WERI-Rb-1 cells and arrested more cells in S phase, which was accompanied by fewer apoptotic cells. Moreover, knockdown of GCN2 induced the constant expression of ATF4 and the phosphorylation of 70S6K and 4E-BP1 regardless of arginine deprivation.

Conclusions: Collectively, our findings suggest that the GCN2‒SLC7A11 axis regulates cell growth and survival upon arginine deprivation through coordinating autophagy, cell cycle arrest, and apoptosis in retinoblastoma cells. This work paves the way for the development of a novel treatment for retinoblastoma.

GCN2-SLC7A11轴协调自噬、细胞周期和细胞凋亡,并在精氨酸缺乏时调节视网膜母细胞瘤的细胞生长。
背景:先前的研究表明,精氨酸剥夺可抑制视网膜母细胞瘤细胞增殖并诱导体外细胞死亡。然而,视网膜母细胞瘤细胞对精氨酸剥夺的反应机制仍有待阐明:方法:对来源于人类的视网膜母细胞瘤细胞株 Y79 和 WERI-Rb-1 进行精氨酸缺失,并评估其对抑制细胞生长和存活的影响。这项研究调查了潜在的机制,包括自噬、细胞周期停滞和细胞凋亡。此外,还研究了一般控制非去极化 2(GCN2)和雷帕霉素复合体 1(mTORC1)信号通路在这些过程中的作用:结果:我们证实,精氨酸剥夺能有效抑制视网膜母细胞瘤细胞在体外的生长。结果:我们证明了精氨酸剥夺能有效抑制视网膜母细胞瘤细胞在体外的生长。此外,长时间的精氨酸缺乏会诱导 G2 细胞周期停滞,并伴随着早期凋亡细胞的增加。重要的是,精氨酸缺失还诱导了 GCN2 的激活和 mTOR 信号转导的抑制。我们还发现,精氨酸缺乏时,SLC7A11 的活化受 GCN2 的调控。敲除 SLC7A11 可使视网膜母细胞瘤细胞对精氨酸匮乏产生部分抵抗力。此外,我们发现敲除 GCN2 会导致 WERI-Rb-1 细胞的自噬反应减弱,更多的细胞停滞在 S 期,同时凋亡细胞减少。此外,无论精氨酸是否被剥夺,敲除 GCN2 都会诱导 ATF4 的持续表达以及 70S6K 和 4E-BP1 的磷酸化:总之,我们的研究结果表明,GCN2-SLC7A11轴通过协调视网膜母细胞瘤细胞的自噬、细胞周期停滞和细胞凋亡,在精氨酸缺乏时调节细胞的生长和存活。这项工作为开发治疗视网膜母细胞瘤的新型疗法铺平了道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
自引率
1.70%
发文量
17
审稿时长
14 weeks
期刊介绍: Cancer & Metabolism welcomes studies on all aspects of the relationship between cancer and metabolism, including: -Molecular biology and genetics of cancer metabolism -Whole-body metabolism, including diabetes and obesity, in relation to cancer -Metabolomics in relation to cancer; -Metabolism-based imaging -Preclinical and clinical studies of metabolism-related cancer therapies.
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