CDK inhibitors (p16/p19/p21) induce senescence and autophagy in cancer-associated fibroblasts, "fueling" tumor growth via paracrine interactions, without an increase in neo-angiogenesis.
CDK inhibitors (p16/p19/p21) induce senescence and autophagy in cancer-associated fibroblasts, "fueling" tumor growth via paracrine interactions, without an increase in neo-angiogenesis.
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DOI：
10.4161/cc.21884
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发表时间：
2012-10-01
期刊：
影响因子：
--
通讯作者：
Lisanti MP
中科院分区：
文献类型：
--
作者：
Capparelli C;Chiavarina B;Whitaker-Menezes D;Pestell TG;Pestell RG;Hulit J;Andò S;Howell A;Martinez-Outschoorn UE;Sotgia F;Lisanti MP
在这里，我们研究了乳腺癌肿瘤生长中细胞周期阻滞和衰老的特定作用。为了这个目的，我们产生了许多hTERT永生化的衰老成纤维细胞系过表达CDK抑制剂，如p16（INK 4A），p19（ARF）或p21（WAF 1/CIP 1）。有趣的是，所有这些衰老的成纤维细胞系都显示出对诱导自噬的易感性增加（在基线或饥饿后）以及显著的线粒体功能障碍的证据。最重要的是，这些衰老的成纤维细胞还显著促进肿瘤生长（高达~2倍），而肿瘤血管生成没有任何可比的增加。相反，我们产生了过表达CDK抑制剂，即p16（INK 4A）或p21（WAF 1/CIP 1）的人乳腺癌细胞（MDA-MB-231细胞）。衰老的MDA-MB-231细胞还显示细胞周期停滞和自噬的标志物（包括β-半乳糖苷酶）的表达增加，如预测的。衰老的MDA-MB-231细胞具有延缓的肿瘤生长，肿瘤体积减少多达接近2倍。因此，CDK抑制剂的作用是区室特异性的，并且与其代谢作用相关，这导致诱导自噬和线粒体功能障碍。最后，用特异性抑制剂（PD 0332991）或细胞应激物[过氧化氢（H2 O2）或饥饿]诱导细胞周期停滞表明自噬和衰老的发生是不可分割地联系在一起的生物过程。隔室特异性诱导衰老（因此自噬）可能是一个新的治疗靶点，可用于成功治疗人类乳腺癌患者。
Here, we investigated the compartment-specific role of cell cycle arrest and senescence in breast cancer tumor growth. For this purpose, we generated a number of hTERT-immortalized senescent fibroblast cell lines overexpressing CDK inhibitors, such as p16(INK4A), p19(ARF) or p21(WAF1/CIP1). Interestingly, all these senescent fibroblast cell lines showed evidence of increased susceptibility toward the induction of autophagy (either at baseline or after starvation), as well as significant mitochondrial dysfunction. Most importantly, these senescent fibroblasts also dramatically promoted tumor growth (up to ~2-fold), without any comparable increases in tumor angiogenesis. Conversely, we generated human breast cancer cells (MDA-MB-231 cells) overexpressing CDK inhibitors, namely p16(INK4A) or p21(WAF1/CIP1). Senescent MDA-MB-231 cells also showed increased expression of markers of cell cycle arrest and autophagy, including β-galactosidase, as predicted. Senescent MDA-MB-231 cells had retarded tumor growth, with up to a near 2-fold reduction in tumor volume. Thus, the effects of CDK inhibitors are compartment-specific and are related to their metabolic effects, which results in the induction of autophagy and mitochondrial dysfunction. Finally, induction of cell cycle arrest with specific inhibitors (PD0332991) or cellular stressors [hydrogen peroxide (H₂O₂) or starvation] indicated that the onset of autophagy and senescence are inextricably linked biological processes. The compartment-specific induction of senescence (and hence autophagy) may be a new therapeutic target that could be exploited for the successful treatment of human breast cancer patients.
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影响因子：
3.9
作者：
Gerland, LM;Peyrol, S;Ffrench, M
通讯作者：
Ffrench, M
影响因子：
4.3
作者：
Blagosklonny, Mikhail V.
通讯作者：
Blagosklonny, Mikhail V.
影响因子：
4.3
作者：
Blagosklonny, Mikhail V.
通讯作者：
Blagosklonny, Mikhail V.
DOI：
10.1073/pnas.211053698
发表时间：
2001-10-09
影响因子：
11.1
作者：
Krtolica, A;Parrinello, S;Campisi, J
通讯作者：
Campisi, J
影响因子：
3.6
作者：
Chiavarina, Barbara;Whitaker-Menezes, Diana;Lisanti, Michael P.
通讯作者：
Lisanti, Michael P.