Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Strong Activation of p53 by Actinomycin D and Nutlin-3a Overcomes Resistance of Cancer Cells to the Pro-apoptotic Activity of FAS Ligand

Barbara Łasut-Szyszka
,
Agnieszka Gdowicz-Kłosok
ORCID logo ,
Małgorzata Krześniak
,
Magdalena Głowala-Kosińska
,
Agnieszka Będzińska
,
Marek Rusin
*
Version 1 : Received: 20 October 2023 / Approved: 23 October 2023 / Online: 25 October 2023 (09:15:59 CEST)
Version 2 : Received: 17 April 2024 / Approved: 18 April 2024 / Online: 18 April 2024 (07:51:28 CEST)

A peer-reviewed article of this Preprint also exists.

Łasut-Szyszka, B.; Gdowicz-Kłosok, A.; Krześniak, M.; Głowala-Kosińska, M.; Będzińska, A.; Rusin, M. Strong Activation of P53 by Actinomycin D and Nutlin-3a Overcomes the Resistance of Cancer Cells to the pro-Apoptotic Activity of the FAS Ligand. Apoptosis 2024, doi:10.1007/s10495-024-02000-0. Łasut-Szyszka, B.; Gdowicz-Kłosok, A.; Krześniak, M.; Głowala-Kosińska, M.; Będzińska, A.; Rusin, M. Strong Activation of P53 by Actinomycin D and Nutlin-3a Overcomes the Resistance of Cancer Cells to the pro-Apoptotic Activity of the FAS Ligand. Apoptosis 2024, doi:10.1007/s10495-024-02000-0.

Abstract

The p53 protein activates pro-apoptotic gene FAS, which encodes death receptor for the FAS ligand (FASLG). Cancer cells are resistant to apoptosis triggered by FASLG. We found that actinomycin D and nutlin-3a (ActD+Nut3a) synergized in activation of p53 and in the induction of pro-apoptotic genes; however, the apoptotic cells were infrequent. We hypothesized that this drug combination sensitizes cancer cells to the pro-apoptotic activity of FASLG. We exposed various cancer cell lines to ActD+Nut3a for 45h and next we treated cells with recombinant FASLG. We observed apoptosis by flow cytometry and by activation status of caspase-3, -8, -9, and -10. The cell viability was determined by the MTS assay and cell staining on culture plates. Actinomycin D and nutlin-3a strongly synergized in sensitizing cells to apoptosis triggered by FASLG. This combination killed more than 99% of cells within 5h. The cell death was accompanied by a strong activation of all examined caspases. In engineered p53-deficient cells this pro-apoptotic effect was completely lost. Therefore, the combination of ActD+Nut3a activates p53 in a way, which overcomes the resistance of cancer cells to apoptosis triggered by FASLG.

Keywords

p53; FASLG; apoptosis; death receptor; MDM2; cancer therapy

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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