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细胞自噬是通过溶酶体途径降解细胞自身成分的一种分解代谢过程,该过程异常可使细胞稳态发生变化,影响多种疾病的发生、发展以及治疗。在血液系统恶性疾病中,细胞自噬不仅在造血干细胞的功能维持中起重要作用,还与化疗药物耐药具有相关性。SQSTM1/P62是参与细胞自噬、肿瘤发生的关键蛋白,其水平与细胞自噬调节密切相关。本文就细胞自噬在血液系统恶性疾病发展中的作用及其对化疗疗效影响的研究进展作一综述。 相似文献
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自噬是细胞内清除受损或多余蛋白和细胞器的一种降解途径,通过对这些物质的重新利用应对细胞内的代谢应激。自噬既参与机体正常生理功能的调节如代谢和免疫等,影响细胞的增殖和死亡,在维护机体的生理平衡和内环境的稳定发挥重要作用;同时还参与多种疾病的发生发展,甚至影响疾病的治疗疗效,目前涉及的疾病主要包括肿瘤、感染和神经退行性变等,其中自噬与肿瘤的相关性研究备受关注。自噬对限制肿瘤坏死与炎症具有保护性作用,也可缓解代谢应激时肿瘤基因组的损伤;相反通过调控自噬水平可影响放化疗的疗效。本文在简要介绍自噬生理功能的基础上,着重阐述自噬介导肿瘤发生发展及治疗。 相似文献
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目的 探讨自噬调控多功能蛋白p62/SQSTM1对非小细胞肺癌生物学行为的影响和调控机制。方法 RT-qPCR检测p62在正常人支气管上皮细胞和非小细胞肺癌细胞中的表达情况;CCK-8、划痕和Transwell实验分别检测抑制和促进p62表达后对非小细胞肺癌细胞增殖、迁移和侵袭能力的影响;Western blot实验检测抑制和促进p62表达后对非小细胞肺癌细胞凋亡相关蛋白(Bcl-2和Bax)和自噬相关蛋白(ATG5和Becline1)表达水平的影响;裸鼠皮下成瘤实验检测抑制p62表达后对非小细胞肺癌细胞体内肿瘤质量的影响。结果 癌旁组织p62表达(1.01±0.08)低于肺癌组织(2.81±0.17)(P <0.05);p62在si-NC、si-p62、pcDNA-NC、pcDNA-p62组的表达水平分别为1.02±0.03、0.62±0.07、1.03±0.01、2.69±0.12。与si-NC组细胞比较,si-p62组细胞中的p62表达显著降低(P <0.05);与pcDNA-NC组细胞比较,pcDNA-p62组细胞中的p62表达显著升高(P <0.05);转染... 相似文献
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《中华临床医师杂志(电子版)》2016,(5)
细胞自噬是细胞在某些刺激因素下,细胞内膜性结构包绕损伤的蛋白或细胞器,并通过溶酶体融合降解损伤的蛋白质或细胞器的过程;生理状况下的自噬,对于维持细胞稳态有积极作用;肿瘤形成以后,细胞自噬反为癌细胞提供更多的营养,起到促进肿瘤发展的功能。自噬主要有三种方式,即分子伴侣介导的自噬、微自噬和巨自噬,均通过两个泛素化途径实现。细胞自噬可以通过影响DNA损伤修复、细胞应激反应、肿瘤基因表达、凋亡及病毒感染反应等诸多过程参与细胞癌变,也可能在肿瘤治疗过程中降低了对于化疗和放疗的敏感性,但是在肿瘤进展的不同时期,不同肿瘤之间自噬活性的变化不一。自噬过程中的重要中间产物或关键酶可能成为抗肿瘤药物的靶标,拓展了肿瘤防治思路。 相似文献
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细胞周期调控异常是肿瘤发生发展的重要机制之一,很多肿瘤标志物的异常表达均能影响细胞的正常增殖从而导致肿瘤的发生。C-JUN激活区结合蛋白1(JAB1)通过与多种蛋白相互作用,参与多种信号途径,在人多种癌症中JAB1表达增高,同时介导p27kip1出核转运及泛素化降解从而降低其在胞浆中的水平,促进肿瘤细胞增殖;Akt在细胞浆的表达增高,使p27kip1磷酸化并抑制p27kip1进入细胞核发挥其生物学功能,Akt也可能参与p27kip1的出核转运及蛋白降解,促进p27kip1降解,进而影响细胞周期的调控,促进肿瘤细胞增殖;抑癌基因p27kip1在肿瘤中表达降低,促使肿瘤细胞增殖;在JAB1介导的p27kip1出核转运中可能有Akt的参与;在HER2介导的PI3K/Akt/p27通路中又有JAB1的参与,三者相互作用形成复杂的网络,共同调节信号转导,促进肿瘤的发生发展。 相似文献
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目的探讨黄芪甲苷对脓毒症大鼠胰腺Beclin1、p62和LC3自噬相关基因和蛋白以及胰腺自噬情况的影响。方法清洁级雄性Wistar大鼠50只,采用随机数字表法分为5组(每组10只):空白对照组(Blank,未加任何干预,直接处死)、生理盐水尾静脉注射组(NS组)、黄芪甲苷低剂量(1 mg/kg)组、黄芪甲苷中剂量(2.5 mg/kg)组、黄芪甲苷高剂量(5 mg/kg)组。采用盲肠结扎穿孔法制造脓毒症模型。利用RT-PCR技术检测各组小鼠胰腺中Beclin1、p62和LC3的mRNA检测水平,Western blotting技术检测各组小鼠胰腺中Beclin1、p62和LC3的蛋白表达水平。采用透射电子显微镜观察胰腺超微结构及腺泡细胞内自噬小体的形成情况。结果与空白对照组相比,NS组大鼠胰腺中的Beclin1、p62和LC3自噬相关基因及蛋白表达明显升高,黄芪甲苷干预后使其表达明显降低,差异均具有统计学意义(P0.05)。电镜显示脓毒症造模24 h,NS组较Blank组胰腺自噬小体明显增多,而黄芪甲苷给药组胰腺自噬小体的形成较NS组明显减少。结论黄芪甲苷能够减少脓毒症大鼠胰腺中Beclin1、p62和LC3基因及蛋白的表达,减少胰腺局部自噬小体的形成。 相似文献
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《中华临床医师杂志(电子版)》2016,(3)
自噬是一个将细胞质中"废物"进行包装,与溶酶体结合的分解代谢过程。自噬的分解代谢是一个循环再利用的过程,它将有毒物质在细胞中清除,剩余有用物质如氨基酸则回收再供细胞利用,从而保持细胞内环境的动态平衡。自噬活性的改变与消化道肿瘤的增殖及迁移有着密切关联,自噬相关基因特别是Beclin1在其中起关键调控作用。了解自噬过程及自噬相关基因Beclin1在消化道肿瘤中的研究现状,希望肿瘤以及自噬相关疾病在未来可以得到解决。 相似文献
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We investigated the effects of the autophagy inhibitor hydroxychloroquine (HCQ) on cell death of cytosine arabinoside (Ara-C)-resistant human acute myeloid leukemia (AML) cells. Ara-C-sensitive (U937, AML-2) and Ara-C-resistant (U937/AR, AML-2/AR) human AML cell lines were used to evaluate HCQ-regulated cytotoxicity, autophagy, and apoptosis as well as effects on cell death-related signaling pathways. We found that HCQ-induced dose- and time-dependent cell death in Ara-C-resistant cells compared to Ara-C-sensitive cell lines. The extent of cell death and features of HCQ-induced autophagic markers including increase in microtubule-associated protein light chain 3 (LC3) I conversion to LC3-II, beclin-1, ATG5, as well as green fluorescent protein-LC3 positive puncta and autophagosome were remarkably greater in U937/AR cells. Also, p62/SQSTM1 was increased in response to HCQ. p62/SQSTM1 protein interacts with both LC3-II and ubiquitin protein and is degraded in autophagosomes. Therefore, a reduction of p62/SQSTM1 indicates increased autophagic degradation, whereas an increase of p62/SQSTM1 by HCQ indicates inhibited autophagic degradation. Knock down of p62/SQSTM1 using siRNA were prevented the HCQ-induced LC3-II protein level as well as significantly reduced the HCQ-induced cell death in U937/AR cells. Also, apoptotic cell death and caspase activation in U937/AR cells were increased by HCQ, provided evidence that HCQ-induced autophagy blockade. Taken together, our data show that HCQ-induced apoptotic cell death in Ara-C-resistant AML cells through autophagy regulation. 相似文献
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Hossein Jalali Atefeh Khoshaeen Mohammad Reza Mahdavi Mahan Mahdavi 《Clinical Case Reports》2022,10(8)
SQSTM1 gene encodes a protein called p62 that acts as an autophagy receptor in the degradation of protein molecules. A homozygous deletion variant that changes the frame shift in the SQSTM1 gene named c.790 Del A .T was detected in case childhood onset and progressive neurodegeneration with ataxia, and gaze palsy. 相似文献
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Shabnam Babataheri Hassan Malekinejad Arash Mosarrezaii Hamid Soraya 《Fundamental & clinical pharmacology》2023,37(3):589-598
Stroke is a serious life-threatening medical condition and is one of the principal reasons for death and disabilities worldwide. The aim of the present study was to determine the neuroprotective effects of hydroxychloroquine (HCQ) and the timing of its administration in cerebral ischemia/reperfusion (I/R) in rats. A global I/R model was used, and HCQ was administered in either pre- or post-treatment doses of 25 and 50 mg/kg. Effects of HCQ on infarct size, histological changes, oxidative stress, and learning and memory were evaluated. Phospho-AMPK and SQSTM1/p62 protein levels were also measured to elucidate the possible mechanisms involved. HCQ in both pre- (at doses of 25 and 50 mg/kg) or post-treatment (at a dose of 50 mg/kg) protocols reduces brain infarct size and histopathological changes and improves learning and memory after cerebral I/R. Pre-treatment with HCQ reduced AMPK activity with no significant effect on SQSTM1/p62 increment. Post-treatment with HCQ increased AMPK activity and SQSTM1/p62 protein levels. Our results show the neuroprotective effects of HCQ on cerebral I/R through the reduction in infarct size, histopathological changes, and improvement in memory and learning functions. Moreover, AMPK and autophagy may play a role in this protective effect. 相似文献
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Eileen White 《The Journal of clinical investigation》2015,125(1):42-46
Autophagy is a survival-promoting pathway that captures, degrades, and recycles intracellular proteins and organelles in lysosomes. Autophagy preserves organelle function, prevents the toxic buildup of cellular waste products, and provides substrates to sustain metabolism in starvation. Although in some contexts autophagy suppresses tumorigenesis, in most contexts autophagy facilitates tumorigenesis. Cancers can upregulate autophagy to survive microenvironmental stress and to increase growth and aggressiveness. Mechanisms by which autophagy promotes cancer include suppressing induction of the p53 tumor suppressor protein and maintaining metabolic function of mitochondria. Efforts to inhibit autophagy to improve cancer therapy have thereby attracted great interest. 相似文献
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自噬是真核生物中细胞对异常蛋白质、细胞器降解的过程,其对正常的细胞与肿瘤细胞的生存都有重要影响。研究表明,自噬广泛存在于骨髓瘤细胞的生命活动中,其不仅能保护骨髓瘤细胞,也能诱导其死亡,对骨髓瘤细胞的生存、增殖、侵袭与迁移以及多发性骨髓瘤的治疗起着重要的作用。本文就调节自噬水平在治疗多发性骨髓瘤中的研究进展作一综述。 相似文献
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自噬是真核细胞中进化上高度保守、用于降解和回收利用细胞内生物大分子和受损细胞器的过程.自噬在细胞应对外界刺激、清除受损物质及细胞生长、分化、死亡中有重要的作用.自噬作为调节机体细胞生长发育和病理生理的重要过程,与多种疾病的发生发展密切相关.研究自噬的发生机制,为开发更多治疗有关疾病的药物提供了理论依据,对疾病的预防和治疗具有重大意义.而微小RNA(miRNA)在多种重要的生命活动过程中扮演着重要角色,对疾病的发生、发展及转归有重要的调节作用.本文介绍一些对自噬有重要调控作用的miRNA,并阐述其在各阶段调控自噬相关基因表达的机制及其对一些疾病的影响. 相似文献