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Open Access 01-12-2015 | Research article

PRIMA-1^MET induces death in soft-tissue sarcomas cell independent of p53

Authors: Thomas Grellety, Audrey Laroche-Clary, Vanessa Chaire, Pauline Lagarde, Frédéric Chibon, Agnes Neuville, Antoine Italiano

Published in: BMC Cancer | Issue 1/2015

Abstract

Background

The aim of this study was to explore the efficacy and define mechanisms of action of PRIMA-1^MET as a TP53 targeted therapy in soft-tissue sarcoma (STS) cells.

Methods

We investigated effects of PRIMA-1^MET on apoptosis, cell cycle, and induction of oxidative stress and autophagy in a panel of 6 STS cell lines with different TP53 status.

Results

Cell viability reduction by PRIMA-1^MET was significantly observed in 5 out of 6 STS cell lines. We found that PRIMA-1^MET was capable to induce cell death not only in STS cells harboring mutated TP53 but also in TP53-null STS cells demonstrating that PRIMA-1^MET can induce cell death independently of TP53 in STS cells. We identified an important role of reactive oxygen species (ROS), involved in PRIMA-1^MET toxicity in STS cells leading to a caspase-independent cell death. ROS toxicity was associated with autophagy induction or JNK pathway activation which represented potential mechanisms of cell death induced by PRIMA-1^MET in STS.

Conclusions

PRIMA-1^MET anti-tumor activity in STS partly results from off-target effects involving ROS toxicity and do not deserve further development as a TP53-targeted therapy in this setting.

Gatta G, van der Zwan JM, Casali PG, Siesling S, Dei Tos AP, Kunkler I, et al. Rare cancers are not so rare: the rare cancer burden in Europe. Eur J Cancer. 2011;47:2493–511.CrossRefPubMed

Clark MA, Fisher C, Judson I, Thomas JM. Soft-tissue sarcomas in adults. N Engl J Med. 2005;353:701–11.CrossRefPubMed

Linch M, Miah AB, Thway K, Judson IR, Benson C. Systemic treatment of soft-tissue sarcoma-gold standard and novel therapies. Nat Rev Clin Oncol. 2014;11:187–202.CrossRefPubMed

Italiano A, Mathoulin-Pelissier S, Cesne AL, Terrier P, Bonvalot S, Collin F, et al. Trends in survival for patients with metastatic soft-tissue sarcoma. Cancer. 2011;117:1049–54.CrossRefPubMed

Bieging KT, Mello SS, Attardi LD. Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer. 2014;14:359–70.CrossRefPubMedPubMedCentral

Pérot G, Chibon F, Montero A, Lagarde P, de Thé H, Terrier P, et al. Constant p53 pathway inactivation in a large series of soft tissue sarcomas with complex genetics. Am J Pathol. 2010;177:2080–90.CrossRefPubMedPubMedCentral

Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2:a001008.CrossRefPubMedPubMedCentral

Lehmann BD, Pietenpol JA. Targeting mutant p53 in human tumors. J Clin Oncol. 2012;30:3648–50.CrossRefPubMed

Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P, et al. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med. 2002;8:282–8.CrossRefPubMed

10.

Lambert JM, Gorzov P, Veprintsev DB, Söderqvist M, Segerbäck D, Bergman J, et al. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell. 2009;15:376–88.CrossRefPubMed

11.

Aryee DN, Niedan S, Ban J, Schwentner R, Muehlbacher K, Kauer M, et al. Variability in functional p53 reactivation by PRIMA-1Met/APR-246 in Ewing sarcoma. Br J Cancer. 2013;109:2696–704.CrossRefPubMedPubMedCentral

12.

Lambert JM, Moshfegh A, Hainaut P, Wiman KG, Bykov VJ. Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010;29:1329–38.CrossRefPubMed

13.

Zandi R, Selivanova G, Christensen CL, Gerds TA, Willumsen BM, Poulsen HS. PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53. Clin Cancer Res. 2011;17:2830–41.CrossRefPubMed

14.

Tansey WP. Freeze-thaw lysis for extraction of proteins from Mammalian cells. CSH Protoc. 2006;2006(7).

15.

Harlow E, Lane D. Lysing tissue-culture cells for immunoprecipitation. CSH Protoc. 2006;2006(4).

16.

Peng X, Zhang MQ, Conserva F, Hosny G, Selivanova G, Bykov VJ, et al. APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase. Cell Death Dis. 2013;4, e881.CrossRefPubMedPubMedCentral

17.

Tessoulin B, Descamps G, Moreau P, Maïga S, Lodé L, Godon C, et al. PRIMA-1Met induces myeloma cell death independently of p53 by impairing the GSH/ROS balance. Blood. 2014;124:1626-36.

18.

Circu ML, Aw TY. Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med. 2010;48:749–62.CrossRefPubMedPubMedCentral

19.

Bao W, Chen M, Zhao X, Kumar R, Spinnler C, Thullberg M, et al. PRIMA-1Met/APR-246 induces wild-type p53-dependent suppression of malignant melanoma tumor growth in 3D culture and in vivo. Cell Cycle. 2011;10:301–7.CrossRefPubMed

20.

Supiot S, Zhao H, Wiman K, Hill RP, Bristow RG. PRIMA-1(met) radiosensitizes prostate cancer cells independent of their MTp53-status. Radiother Oncol. 2008;86:407–11.CrossRefPubMed

21.

Sobhani M, Abdib J, Chenc C, Changa H. PRIMA-1Met induces apoptosis in Waldenström’s Macroglobulinemia cells independent of p53. Cancer Biol Ther. 2015;16:799–806.CrossRefPubMedPubMedCentral

22.

Chipuk JE, Maurer U, Green DR, Schuler M. Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription. Cancer Cell. 2003;4:371–81.CrossRefPubMed

23.

Shen J, Vakifahmetoglu H, Stridh H, Zhivotovsky B, Wiman KG. PRIMA-1^MET induces mitochondrial apoptosis through activation of caspase-2. Oncogene. 2008;27:6571–80.CrossRefPubMed

24.

Miwa S, Muller FL, Beckman KB. The Basics of Oxidative Biochemistry. In Oxidative Stress in Aging; 2008. p. 11–35.

25.

Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev. 2010;90:1383–435.CrossRefPubMed

26.

Russo D, Ottaggio L, Foggetti G, Masini M, Masiello P, Fronza G, et al. PRIMA-1 induces autophagy in cancer cells carrying mutant or wild type p53. Biochim Biophys Acta. 1833;2013:1904–13.

27.

Loos B, Engelbrecht AM, Lockshin RA, Klionsky DJ, Zakeri Z. The variability of autophagy and cell death susceptibility: unanswered questions. Autophagy. 2013;9:1270–85.CrossRefPubMedPubMedCentral

28.

Cano E, Hazzalin CA, Mahadevan LC. Anisomycin-activated protein kinases p45 and p55 but not mitogen-activated protein kinases ERK-1 and −2 are implicated in the induction of c-fos and c-jun. Mol Cell Biol. 1994;14:7352–62.23.CrossRefPubMedPubMedCentral

29.

Ryter SW, Kim HP, Hoetzel A, Park JW, Nakahira K, Wang X, et al. Mechanisms of cell death in oxidative stress. Antioxid Redox Signal. 2007;9:49–89.CrossRefPubMed

30.

Li Y, Mao Y, Brandt-Rauf PW, Williams AC, Fine RL. Selective induction of apoptosis in mutant p53 premalignant and malignant cancer cells by PRIMA-1 through the c-Jun-NH2-kinase pathway. Mol Cancer Ther. 2005;4:901–9.CrossRefPubMed

31.

Tsang WP, Chau SP, Kong SK, Fung KP, Kwok TT. Reactive oxygen species mediate doxorubicin induced p53-independent apoptosis. Life Sci. 2003;73:2047–58.CrossRefPubMed

Title: PRIMA-1MET induces death in soft-tissue sarcomas cell independent of p53
Authors: Thomas Grellety
Audrey Laroche-Clary
Vanessa Chaire
Pauline Lagarde
Frédéric Chibon
Agnes Neuville
Antoine Italiano
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-015-1667-1

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Abstract

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Conclusions

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