干扰素在肿瘤细胞凋亡信号传导通路中的作用及影响

干扰素（IFN）是一类具有抗病毒、抗肿瘤和免疫调节作用的细胞因子。近年来研究发现,IFN与肿瘤细胞表面受体结合后,主要通过JAK／STAT信号途径来调节一系列IFN刺激基因的表达,影响肿瘤细胞凋亡传导通路及某些凋亡调节因子,增强肿瘤细胞对凋亡信号的敏感性,诱导肿瘤细胞凋亡,从而发挥抗肿瘤效应。     

干扰素诱导肿瘤凋亡的分子机制

干扰素（interferons，IFNs）是一类重要的抗病毒、抗肿瘤和免疫调节细胞因子。IFNs广泛用于造血系统恶性肿瘤、淋巴瘤及多种实体瘤的临床治疗。IFNs与细胞表面受体结合后，主要通过JAK／STAT信号途径，调节一系列干扰素刺激基因（IFN-stimulated genes，ISGs）表达，这些功能性基因包括凋亡相关分子Fas／FasL、TRAIL／APO-2、抑癌基因bax、bak及p53等，这些ISGs与细胞凋亡及抑制细胞周期密切相关。此外，IFN还可放大由caspase诱导的线粒体功能紊乱效应，诱导细胞经线粒体途径凋亡。因而，IFNs主要通过抑制细胞周期、诱导抑癌基因的表达及增强肿瘤细胞对凋亡信号敏感性，诱导肿瘤细胞凋亡，而发挥其抗肿瘤生物学活性。     

干扰素诱导肿瘤凋亡的分子机制

干扰素(interferons,IFNs)是一类重要的抗病毒、抗肿瘤和免疫调节细胞因子。IFNs广泛用于造血系统恶性肿瘤、淋巴瘤及多种实体瘤的临床治疗。IFNs与细胞表面受体结合后,主要通过JAK/STAT信号途径,调节一系列干扰素刺激基因(IFN-sti mulated genes,ISGs)表达,这些功能性基因包括凋亡相关分子Fas/FasL、TRAIL/APO-2、抑癌基因bax、bak及p53等,这些ISGs与细胞凋亡及抑制细胞周期密切相关。此外,IFN还可放大由caspase诱导的线粒体功能紊乱效应,诱导细胞经线粒体途径凋亡。因而,IFNs主要通过抑制细胞周期、诱导抑癌基因的表达及增强肿瘤细胞对凋亡信号敏感性,诱导肿瘤细胞凋亡,而发挥其抗肿瘤生物学活性。     

TRAIL作用机制及其在肿瘤治疗中的研究

肿瘤坏死因子相关凋亡诱导配体(TRAIL)具有特异性抗肿瘤活性,可通过死亡受体途径及转录因子途径发挥诱导肿瘤细胞凋亡作用.而正常细胞则通过诱骗受体、FLIP及凋亡抑制蛋白来逃逸TRAIL诱导的凋亡.TRAIL与化疗药物、基因治疗联合应用能明显提高肿瘤治疗的靶向性,同时还可以逆转肿瘤细胞对TRAIL的抵抗现象.因此TRAIL作为新型抗肿瘤药物有望应用于临床治疗.     

多糖诱导肿瘤细胞凋亡机制的研究进展

多糖是普遍存在于动物、植物和微生物中的大分子物质,在细胞识别、信号传导、调节肌体免疫及细胞的迁移、增殖、分化和代谢等方面均有十分重要的作用。近年来众多研究结果表明,多糖可抗肿瘤活性,抑制多种肿瘤细胞生长。究其机制,多糖除可诱导免疫因子生成,增强机体免疫功能外,还能直接杀死肿瘤细胞。通过阐述动物、植物和微生物多糖可以诱导多种肿瘤细胞凋亡,说明多糖具有广谱抑制肿瘤细胞生长的作用;初步探讨了多糖诱导肿瘤细胞凋亡的机制,例如激活死亡受体途径和线粒体途径,调控凋亡基因,调节端粒酶和拓扑酶等。     

白头翁皂苷D抗肿瘤的研究进展

白头翁皂苷D是白头翁众多有效单体成分中在抗肿瘤方面研究最广泛、效价最高的单体,是近年来抗肿瘤药物研究的热点之一。白头翁皂苷D通过抑制肿瘤细胞增殖、促进肿瘤细胞凋亡、抑制能量代谢、调节自噬以及抑制肿瘤细胞迁移和转移等方面抑制肿瘤生存,现就近年来白头翁皂苷D抗肿瘤方面的相关研究进行综述。     

干扰素与TRAIL在诱导肿瘤细胞凋亡中的相互作用

干扰素(IFN)和肿瘤坏死因子相关凋亡诱导配体(TRAIL)均可诱导肿瘤细胞凋亡,但两者作用机制不同,而且并不是所有肿瘤细胞都对它们诱导的凋亡作用敏感。已有研究发现二者共同作用具有协同诱导细胞凋亡的作用,并可使原先对单一物质抵抗的肿瘤细胞变得敏感,从而达到治疗的目的。     

双氢青蒿素的抗肿瘤作用机制

双氢青蒿素是青蒿的活性成分之一,可通过与铁离子形成自由基杀伤肿瘤细胞、诱导细胞凋亡、抗肿瘤血管生成、抑制肿瘤侵袭转移、逆转多药耐药、影响细胞内Ca2浓度、调控细胞周期、调节细胞自噬和免疫系统等方式参与抗肿瘤过程,是潜在可利用的抗肿瘤新药.     

TLR4与肿瘤细胞凋亡相关性的研究进展

Toll样受体4（TLR4）作为一种模式识别受体,是近年来肿瘤免疫学的研究热点之一,其在抑制肿瘤细胞凋亡调控上扮演着重要角色。TLR4主要通过两个信号通路对肿瘤细胞凋亡进行调节,其一为TLR4通过MyD88蛋白调节核转录因子kappa B（NF-κB）产生,促进肿瘤细胞增殖;其二为TLR4通过PI3K／Akt信号通路来抑制肿瘤细胞凋亡。现就近年来TLR4与肿瘤细胞凋亡相关性的研究进行综述。     

干扰素与TRAIL在诱导肿瘤细胞凋亡中的相互作用

干扰素（IFN）和肿瘤坏死因子相关凋亡诱导配体（TRAIL）均可诱导肿瘤细胞凋亡，但两者作用机制不同，而且并不是所有肿瘤细胞都对它们诱导的凋亡作用敏感。已有研究发现二者共同作用具有协同诱导细胞凋亡的作用，并可使原先对单一物质抵抗的肿瘤细胞变得敏感，从而达到治疗的目的。     

Signaling through IFN regulatory factor-5 sensitizes p53-deficient tumors to DNA damage-induced apoptosis and cell death

Human IFN regulatory factor-5 (IRF-5) is a candidate tumor suppressor gene that mediates cell arrest, apoptosis, and immune activation. Here we show that ectopic IRF-5 sensitizes p53-proficient and p53-deficient colon cancer cells to DNA damage-induced apoptosis. The combination IFN-beta and irinotecan (CPT-11) cooperatively inhibits cell growth and IRF-5 synergizes with it to further promote apoptosis. The synergism is due to IRF-5 signaling since a striking defect in apoptosis and cell death was observed in IRF-5-deficient cells, which correlated well with a reduction in DNA damage-induced cellular events. Components of this IRF-5 signaling pathway are investigated including a mechanism for DNA damage-induced IRF-5 activation. Thus, IRF-5-regulated pathways may serve as a target for cancer therapeutics.     

Type III interferon induces apoptosis in human lung cancer cells

The apoptotic effects of interferon lambdas (IFNλs) have been described in several types of cancers. However, their effects on human lung cancer cells and the mechanisms are elusive. In addition, the interaction between IFNλs and other interferons remains unclear. The interplay between IFNα and IFNλ has been reported. However, although IFNγ is a well-known regulatory interferon, the mechanisms through which it regulates IFNλs in lung cancer cells are unknown. These issues are critical for the application of IFNλs in lung cancer therapy. In this study, we used A549, a cell line derived from a human lung carcinoma, to characterize the antiproliferative and apoptotic effects of IFNλs on lung cancer, and the interplay between IFNγ and IFNλ. Because overexpression of full-length ectopic IFNλR1 led to cell death, we generated A549 cells stably expressing a chimeric receptor (10R1/λR1), which is composed of the extracellular domain of IL-10 receptor (IL10R1) fused in tandem to the transmembrane and intracellular domains of the IFNλ receptor (IFNλR1). By comparing with A549 cells stably expressing its cognate vector, we demonstrated that IL-10 stimulation triggered the intracellular IFNλ signaling via 10R1/λR1 receptor. By using A549 cells expressing 10R1/λR1, we report that the IFNλR1 chain of IFNλ receptor possesses an intrinsic ability to trigger apoptosis in human lung cancer cells. Although it did not suppress cell proliferation, IFNλ signaling via 10R1/λR1 receptor induced cell cycle arrest, externalization of phosphatidylserine, DNA fragmentation, activation of caspase-3, caspase-8 and caspase-9. However, the caspase inhibitor Z-VAD-FMK did not prevent apoptosis. In addition, the extent of induced apoptosis correlate with the expression levels of the IFNλ receptor and the levels of STAT1 activation. Lastly, we demonstrated that IFNγ sensitized A549 cells to IFNλ-induced apoptosis, via upregulation of IFNλR1. These data indicate the potential of IFNλ, alone or in combination with IFNγ, in the treatment of human lung carcinoma.     

Role of Apo2L/TRAIL and Bcl-2-family proteins in apoptosis of multiple myeloma

Apo2 Ligand or Tumour Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (Apo2L/TRAIL) is a member of the TNF gene superfamily that selectively induces apoptosis in tumor cells of diverse origins through engagement of death receptors. We have recently demonstrated that Type I interferons (IFN-alpha and beta) induce apoptosis in multiple myeloma (MM) cell lines and in plasma cells from MM patients. Moreover, Apo2L selectively induces apoptosis of patient MM tumor cells while sparing non-malignant cells. Apo2L induction is one of the earliest events following IFN administration in these cells. IFNs activate Caspases and the mitochondrial-dependent apoptotic pathway mediated by Apo2L production. Cell death induced by IFNs and Apo2L can be blocked by a dominant-negative Apo2L receptor, DRS, and is regulated by members of the Bcl-2 family of proteins. This review is focused on the apoptotic signaling pathways regulated by Apo2L and Bcl-2-family proteins and summarizes what is known about their clinical role.