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J Invest Dermatol. 2014 Jun;134(6):1686-1692. doi: 10.1038/jid.2014.18. Epub 2014 Jan 16.

Caspase 3 promotes surviving melanoma tumor cell growth after cytotoxic therapy.

Author information

1
Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA; Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
2
Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA; Cancer Center, First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
3
Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA.
4
Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA. Electronic address: chuan.li@duke.edu.

Abstract

Metastatic melanoma often relapses despite cytotoxic treatment, and hence the understanding of melanoma tumor repopulation is crucial for improving our current therapies. In this study, we aim to define the role of caspase 3 in melanoma tumor growth after cytotoxic therapy. We examined a paradigm-changing hypothesis that dying melanoma cells undergoing apoptosis during cytotoxic treatment activate paracrine signaling events that promote the growth of surviving tumor cells. We propose that caspase 3 has a key role in the initiation of the release of signals from dying cells to stimulate melanoma tumor growth. We created a model for tumor cell repopulation in which a small number of luciferase-labeled, untreated melanoma cells are seeded onto a layer of a larger number of unlabeled, lethally treated melanoma cells. We found that dying melanoma cells significantly stimulate the growth of living melanoma cells in vitro and in vivo. Furthermore, we observed that caspase 3 gene knockdown attenuated the growth-stimulating effect of irradiated, dying cells on living melanoma cell growth. Finally, we showed that caspase 3-mediated dying melanoma cell stimulation of living cell growth involves secreted prostaglandin E2 (PGE2). Our study therefore suggests a counterintuitive strategy to inhibit caspase 3 for therapeutic gain in melanoma treatment.

PMID:
24434746
PMCID:
PMC4020991
DOI:
10.1038/jid.2014.18
[Indexed for MEDLINE]
Free PMC Article

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