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

Abstract

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.

A Cell’s Fate: An Overview of the Molecular Biology and Genetics of Apoptosis

“…This protein activates the extrinsic pathway by inducing FAS and promoting apoptosis through an element located in intron 1, which binds to FAS promoter regions and reaches maximum transactivation [106]. Its mechanisms through DNA damage may also be implicated in DR5 activation and consequent activation of CASP8 and Poly ADP-ribose polymerase (PARP), with this relationship being a potential therapeutic target in cancer treatment [107]. Recently, a component named Ziyuglycoside I (Ziyu I) was reported to be capable of inducing mitochondrial dependent apoptosis in human WERI-Rb-1 Retinoblastoma cells due to increased expression of p53 [108].…”

Akkermansia muciniphila Aspartic Protease Amuc_1434* Inhibits Human Colorectal Cancer LS174T Cell Viability via TRAIL-Mediated Apoptosis Pathway

“…Thus, the downregulation of Bcl-2 protein may also be a reason for the increased p53 expression. Additionally, p53 negatively regulates Muc2 and participates in the TRAIL mediated apoptotic pathway [9][10][11][12][13][14][15], so the upregulation of TRAIL by Amuc_1434* may be a reason for its degradation of Muc2. In addition, studies have shown that there is negative regulation between Bcl-2 protein and intracellular ROS [32].…”

“…Mutation of p53, which is a tumor-suppressor gene, is responsible for 70% of CRC cases, so failure of apoptosis is a major factor in the transition from adenoma to CRC [12,13]. p53 also participates in the tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptotic pathway, which plays a role in the apoptotic process of colorectal cancer cells [14,15]. As a result, activation of the apoptosis of colon cells is of vital importance for controlling the progression of CRC [16].…”

p53-Mediated Oxidative Stress Enhances Indirubin-3′-Monoxime-Induced Apoptosis in HCT116 Colon Cancer Cells by Upregulating Death Receptor 5 and TNF-Related Apoptosis-Inducing Ligand Expression

“…Particularly, the tumor suppressor p53, is well known to positively modulate TRAIL expression by binding to the promoter region of TRAIL at 346 and 625 bp upstream of the transcription start site, suggesting that it triggers TRAIL-mediated cancer cell death [21]. Recently, Willms et al, also reported that because p53 can activate apoptotic proteins such as Bax and Bid, it is an important inducer of DR-mediated apoptosis in cancer cells [22]. This study revealed that I3M enhanced apoptosis in HCT116 p53 +/+ cells by activating DR5 and TRAIL expression.…”