文章：

肿瘤细胞凋亡和非凋亡性死亡的途径

Pathways of apoptotic and non-apoptotic death in tumour cells

原文发布日期：2004-08-01

DOI: 10.1038/nrc1412

类型: Review Article

开放获取: 否

要点：

1. Resistance to apoptosis is considered to be a hallmark of cancer cells. Defects in apoptosis underlie not only tumorigenesis, but also resistance to cancer treatments.
2. Defects in non-apoptotic cell-death pathways — such as necrosis, autophagy and mitotic catastrophe — are also associated with tumorigenesis. The senescence 'living-death' programme — which involves the genes that encode p53, WAF1, INK4A and the retinoblastoma protein — is crucial for both tumour suppression and anticancer therapy.
3. Malignant transformation can be induced by the dysregulation of oncogenes and tumour-suppressor genes that have secondary functions in the autophagic pathway. Inactivation of the autophagy gene beclin 1 induces malignancy in a mouse model.
4. Defects in genes that are required for mitotic catastrophe can contribute to tumorigenesis. Uncontrolled activation of mitotic kinases and defects in mitotic checkpoints are important causes of centrosomal aberrations and genomic instability.
5. Survivin is essential for mitotic progression, and inactivation of this protein induces death by mitotic catastrophe. Survivin might be an ideal target for cancer treatment, because cell death induced by survivin loss is independent of BCL2 and p53.
6. The interactions between non-apoptotic and apoptotic cell-death pathways are not yet clear. Further investigation of non-apoptotic pathways might reveal new targets for the design of therapeutics that are aimed at inducing the non-apoptotic death of cancer cells.

要点翻译：

1. 对凋亡的抵抗被视为癌细胞的一个标志性特征。凋亡缺陷不仅是肿瘤发生的基础，也是癌症治疗耐药性的根源。
2. 非凋亡性细胞死亡途径（如坏死、自噬和有丝分裂灾难）的缺陷也与肿瘤发生相关。衰老"活死亡"程序——涉及编码p53、WAF1、INK4A和视网膜母细胞瘤蛋白的基因——对肿瘤抑制和抗癌治疗都至关重要。
3. 恶性转化可由在自噬途径中具有次要功能的癌基因和肿瘤抑制基因失调所诱导。自噬基因beclin 1的失活可在小鼠模型中诱发恶性肿瘤。
4. 有丝分裂灾难所需基因的缺陷可能促进肿瘤发生。有丝分裂激酶的失控激活和有丝分裂检查点的缺陷是中心体畸变和基因组不稳定的重要原因。
5. 生存素对有丝分裂进程至关重要，该蛋白的失活会通过有丝分裂灾难诱导死亡。生存素可能是癌症治疗的理想靶点，因为生存素缺失诱导的细胞死亡不依赖于BCL2和p53。
6. 非凋亡性与凋亡性细胞死亡途径之间的相互作用尚不清楚。对非凋亡途径的进一步研究可能为设计旨在诱导癌细胞非凋亡性死亡的疗法揭示新靶点。

英文摘要：

Defects in cell-death pathways are hallmarks of cancer. Although resistance to apoptosis is closely linked to tumorigenesis, tumour cells can still be induced to die by non-apoptotic mechanisms, such as necrosis, senescence, autophagy and mitotic catastrophe. The molecular pathways that underlie these non-apoptotic responses remain unclear. Several apoptotic and non-apoptotic pathways of cell death have been defined in normal physiology and during tumorigenesis, and these could potentially be manipulated to develop new cancer therapies. The mitotic-checkpoint molecule survivin — the inactivation of which induces the death of p53-deficient cells by mitotic catastrophe — is of particular interest.

摘要翻译： 

细胞死亡通路的缺陷是癌症的标志。尽管对凋亡的抵抗与肿瘤发生密切相关，但肿瘤细胞仍可通过非凋亡机制（如坏死、衰老、自噬和有丝分裂灾难）被诱导死亡。这些非凋亡反应背后的分子通路仍不清楚。在正常生理和肿瘤发生过程中，已定义了多种凋亡和非凋亡的细胞死亡通路，这些通路有可能被利用来开发新的癌症疗法。有丝分裂检查点分子survivin——其失活可通过有丝分裂灾难诱导p53缺陷细胞死亡——尤为值得关注。

原文链接：

Pathways of apoptotic and non-apoptotic death in tumour cells