Apoptotic Cells Activate the "Phoenix Rising" Pathway to Promote Wound Healing and Tissue Regeneration

Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Science Signaling (Impact Factor: 6.28). 02/2010; 3(110):ra13. DOI: 10.1126/scisignal.2000634
Source: PubMed


The ability to regenerate damaged tissues is a common characteristic of multicellular organisms. We report a role for apoptotic cell death in promoting wound healing and tissue regeneration in mice. Apoptotic cells released growth signals that stimulated the proliferation of progenitor or stem cells. Key players in this process were caspases 3 and 7, proteases activated during the execution phase of apoptosis that contribute to cell death. Mice lacking either of these caspases were deficient in skin wound healing and in liver regeneration. Prostaglandin E(2), a promoter of stem or progenitor cell proliferation and tissue regeneration, acted downstream of the caspases. We propose to call the pathway by which executioner caspases in apoptotic cells promote wound healing and tissue regeneration in multicellular organisms the "phoenix rising" pathway.

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    • "Therefore, we sought to study the role of dying cell stimulation of living tumor cell growth in pancreatic cancer. In particular , we previously observed that when a small number of living tumor cells were seeded onto a much larger number of irradiated, dying tumor cells, the dying cells stimulated the growth of living tumor cells (Huang et al., 2011; Li et al., 2010). We discovered the " Phoenix Rising " pathway of dying cell stimulation of living tumor cell growth, which involves the release of paracrine signals resulting in proliferation of the living tumor cells. "
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    ABSTRACT: Pancreatic cancer is one of the most lethal human cancers, and radiotherapy is often implemented for locally advanced pancreatic ductal adenocarcinoma. Tumor cell repopulation is a major challenge in treating cancers after radiotherapy. In order to address the problem of tumor repopulation, our previous studies have demonstrated that dying cells stimulate the proliferation of living tumor cells after radiotherapy. In particular, dying cells undergoing apoptosis also activate survival or proliferation signals and release growth factors to surrounding living cells. In the present study, we used an in vitro model to examine the possible mechanisms for dying cell stimulated tumor repopulation in pancreatic cancer. In this model, a small number of living, luciferase-labeled pancreatic cancer cells (reporter) were seeded onto a layer of a much larger number of irradiated, unlabeled pancreatic cancer cells and the growth of the living cells was measured over time as a gage of tumor repopulation. Our results indicate that irradiated, dying Panc1 feeder cells significantly stimulated the proliferation of living Panc1 reporter cells. Importantly, we identified that the percentage of apoptotic cells and the cleavage of caspases 3 and 7 and protein kinase Cδ (PKCδ) were increased in irradiated Panc1 cells. We presumed that caspases 3 and 7 and PKCδ as integral mediators in the process of dying pancreatic cancer cell stimulation of living tumor cell growth. In order to demonstrate the importance of caspases 3, 7 and PKCδ, we introduced dominant-negative mutants of caspase 3 (DN_C3), caspase 7 (DN_C7), or PKCδ (DN_PKCδ) into Panc1 cells using lentiviral vectors. The stably transduced Panc1 cells were irradiated and used as feeders and we found a significant decrease in the growth of living Panc1 reporter cells when compared with irradiated wild-type Panc1 cells as feeders. Moreover, the role of PKCδ in the growth stimulation of living tumor cells was further confirmed using a pan PKC inhibitor GF109203x and a specific PKCδ inhibitor, rottlerin. Additionally, we found significantly increased phosphorylation of Akt, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase/stress-activated protein kinase (JNK1/2) in the irradiated Panc1 cells. Mechanistically, PKCδ cleavage was attenuated in both DN_C3 and DN_C7 transduced Panc1 cells, and both Akt and p38 MAPK phosphorylation were attenuated in DN_PKCδ transduced Panc1 cells following radiation. Thus, this report suggests a novel finding that cellular signaling caspase 3/7-PKCδ-Akt/p38 MAPK is crucial to the repopulation in Panc1 cells after radiotherapy.
    Molecular Oncology 01/2015; 9(1):105-114. DOI:10.1016/j.molonc.2014.07.024 · 5.33 Impact Factor
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    • "). Similarly , apoptotic cell death has been shown to promote wound healing and tissue regeneration via a pathway referred to as the " phoenix rising " pathway (Li et al., 2010). In the case of the BK5.EP4 mice, this pathway is facilitated by the upregulation of pro-inflammatory and proliferation-related genes. "
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    ABSTRACT: Pharmacological and genetic approaches have shown that prostaglandins (PGs) synthesized by cyclooxygenase-2 (COX-2) have tumor promoting/progression activity in murine skin. To determine whether the EP4 receptor for PGE2 contributes to this tumor promoting/progression activity, EP4 over-expressing mice (BK5.EP4) were generated and subjected to several carcinogenesis protocols. A two-stage 7,12-dimethylbenz[a]anthracene (DMBA)-12-O-tetradecanoylphorbol-13-acetate (TPA) protocol resulted in 25-fold more squamous cell carcinomas (SCCs) in the BK5.EP4 mice than wild type (WT) mice. A similar increase in SCCs was observed following treatment with DMBA alone (no TPA) and following UV irradiation. DMBA caused a cytotoxicity in BK5.EP4, but not WT mice, that was characterized by increased apoptosis, increased metalloproteinase(MMP)-9 and MMP-7 expression, and sloughing of the interfollicular epidermis, followed by regeneration and SCC development. An analysis of cytochrome P450 levels, wound healing time and keratinocyte stem cells showed no difference between BK5.EP4 and WT mice. A comparison of transcriptomes between BK5.EP4 and WT mice treated with PGE2 showed a significant upregulation of a number of genes known to be associated with tumor development, including interleukin-20 (IL-20), which was verified at the protein level, supporting a pro-tumorigenic role for the EP4 receptor.
    Molecular Oncology 12/2014; 8(8). DOI:10.1016/j.molonc.2014.06.013 · 5.33 Impact Factor
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    • "Although cell stress and apoptosis logically seems detrimental to the well being of the cells, it has been shown to be a positive force in the context of regeneration . For example, regeneration is found to be defective when apoptosis is blocked with caspase inhibitors in planaria [12], hydra heads [14], Drosophila [15] [19] [20], zebrafish fins [21], X. laevis tails [13], and mouse livers [22]. Overall, this suggests that stressed-induced apoptosis , partially caused from oxidative stress, activates local cell proliferation to support regeneration (Fig. 1). "
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    ABSTRACT: Injury is an inescapable phenomenon of life that affects animals at every physiological level. Yet, some animals respond to injury by rebuilding the damaged tissues whereas others are limited to scarring. Elucidating how a tissue insult from wounding leads to a regenerative response at the genetic level is essential to make regenerative advantages translational. It has become clear that animals with regenerative abilities recycle developmental programs after injury, reactivating genes that have lied dormant throughout adulthood. The question that is critical to our understanding of regeneration is how a specific set of developmentally important genes can be reactivated only after an acute tissue insult. Here, we review how injury-induced cellular stresses such as hypoxic, oxidative, and mechanical stress may contribute to the genomic and epigenetic changes that promote regeneration in animals. This article is part of a Special Issue entitled: Stress as a fundamental theme in cell plasticity.
    Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 07/2014; 1849(4). DOI:10.1016/j.bbagrm.2014.07.021 · 6.33 Impact Factor
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