Impact of p53 status on TRAIL-mediated apoptotic and non-apoptotic signaling in cancer cells

被引:35
|
作者
Willms, Anna [1 ]
Schittek, Hella [1 ]
Rahn, Sascha [1 ]
Sosna, Justyna [2 ,4 ]
Mert, Ufuk [1 ]
Adam, Dieter [2 ]
Trauzold, Anna [1 ,3 ]
机构
[1] Univ Kiel, Inst Expt Canc Res, CCC North, Div Mol Oncol, Kiel, Germany
[2] Univ Kiel, Inst Immunol, Kiel, Germany
[3] Univ Hosp Schleswig Holstein, Clin Gen Surg Visceral Thorac Transplantat & Pedi, Kiel, Germany
[4] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92717 USA
来源
PLOS ONE | 2019年 / 14卷 / 04期
关键词
DEATH; RECEPTORS; PROMOTES; PROLIFERATION; EXPRESSION; MATURATION; RESISTANCE; MIGRATION; INVASION; TARGET;
D O I
10.1371/journal.pone.0214847
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Due to their ability to preferentially induce cell death in tumor cells, while sparing healthy cells, TNF-related apoptosis-inducing ligand (TRAIL) and agonistic anti-TRAIL-R1 or anti-TRAIL-R2-specific antibodies are under clinical investigations for cancer-treatment. However, TRAIL-Rs may also induce signaling pathways, which result in malignant progression. TRAIL receptors are transcriptionally upregulated via wild-type p53 following radio- or chemotherapy. Nevertheless, the impact of p53 status on the expression and signaling of TRAIL-Rs is not fully understood. Therefore, we analyzed side by side apoptotic and non-apoptotic signaling induced by TRAIL or the agonistic TRAIL-R-specific antibodies Mapatumumab (anti-TRAIL-R1) and Lexatumumab (anti-TRAIL-R2) in the two isogenic colon carcinoma cell lines HCT116 p53(+/+) and p53(-/-). We found that HCT116 p53(+/+) cells were significantly more sensitive to TRAIL-R-triggering than p53(-/-)cells. Similarly, A549 lung cancer cells expressing wild-type p53 were more sensitive to TRAIL-R-mediated cell death than their derivatives with knockdown of p53. Our data demonstrate that the contribution of p53 in regulating TRAIL-R-induced apoptosis does not correlate to the levels of TRAIL-Rs at the plasma membrane, but rather to p53-mediated upregulation of Bax, favouring the mitochondrial amplification loop. Consistently, stronger caspase-9 and caspase-3 activation as well as PARP-cleavage was observed following TRAIL-R-triggering in HCT116 p53(+/+) compared to HCT116 p53(-/-)- cells. Interestingly, HCT116 p53(+/+) cells showed also a more potent activation of non-canonical TRAIL-R-induced signal transduction pathways like JNK, p38 and ERK1/ERK2 than p53(-/-) cells. Likewise, these cells induced IL-8 expression in response to TRAIL, Mapatumumab or Lexatumumab significantly stronger than p53(-/-)- cells. We obtained similar results in A549 cells with or without p53-knockdown and in the two isogenic colon cancer cell lines RKO p53(+/+) and p53(-/-). In both cellular systems, we could clearly demonstrate the potentiating effects of p53 on TRAIL-R-mediated IL-8 induction. In conclusion, we found that wild-type p53 increases TRAIL-R-mediated apoptosis but simultaneously augments non-apoptotic signaling.
引用
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页数:17
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