MDM2 inhibitor nutlin-3a induces apoptosis and senescence in cutaneous T-cell lymphoma: Role of p53

Valentina Manfé; Edyta Urszula Biskup; Peter Johansen; Maria Rørbæk Kamstrup; Thorbjørn Frej Krejsgaard; Niels Morling; Hans Chr. Wulf; Robert Gniadecki

doi:10.1038/jid.2012.10

MDM2 inhibitor nutlin-3a induces apoptosis and senescence in cutaneous T-cell lymphoma: Role of p53

Valentina Manfé, Edyta Urszula Biskup, Peter Johansen, Maria Rørbæk Kamstrup, Thorbjørn Frej Krejsgaard, Niels Morling, Hans Chr. Wulf, Robert Gniadecki

29 Citations (Scopus)

Abstract

P53 is rarely mutated in cutaneous T-cell lymphoma (CTCL) and is therefore a promising target for innovative therapeutic approaches. Nutlin-3a is an inhibitor of MDM2 (human homolog of murine double minute 2), which disrupts its interaction with p53, leading to the stabilization and activation of p53. To investigate the potential therapeutic use of nutlin-3a in CTCL, we screened CTCL lines Hut-78, SeAx, MyLa2000, Mac1, and Mac2a by measuring p53 levels after nutlin-3a treatment. In MyLa2000, Mac1, and Mac2a, we observed the increase in p53, indicating the fully functional p53. In the remaining cell lines, P53 mutation analysis identified a homozygous nonsense mutation (R196Stop in Hut-78) and a homozygous missense mutation (G245S in SeAx). In MyLa2000, Mac1, and Mac2a carrying wild-type P53, nutlin-3a induced apoptosis and senescence demonstrated by permanent G0/G1 cell-cycle block and expression of the senescence-associated Β-galactosidase. This effect was abolished in cells in which p53 was silenced by small interfering RNA. Sézary cells lack functional p53 and were resistant to nutlin-3a. However, nutlin-3a potentiated the efficacy of conventional chemotherapeutics not only in cells with intact p53 but also in Hut-78, SeAx, and Sézary cells. Thus, targeting p53 by nutlin-3a may constitute a therapeutic approach in CTCL because of increased apoptosis and senescence of tumor cells.

Original language	English
Journal	Journal of Investigative Dermatology
Volume	132
Pages (from-to)	1487-1496
Number of pages	9
ISSN	0022-202X
DOIs	https://doi.org/10.1038/jid.2012.10
Publication status	Published - May 2012

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title = "MDM2 inhibitor nutlin-3a induces apoptosis and senescence in cutaneous T-cell lymphoma: Role of p53",

abstract = "P53 is rarely mutated in cutaneous T-cell lymphoma (CTCL) and is therefore a promising target for innovative therapeutic approaches. Nutlin-3a is an inhibitor of MDM2 (human homolog of murine double minute 2), which disrupts its interaction with p53, leading to the stabilization and activation of p53. To investigate the potential therapeutic use of nutlin-3a in CTCL, we screened CTCL lines Hut-78, SeAx, MyLa2000, Mac1, and Mac2a by measuring p53 levels after nutlin-3a treatment. In MyLa2000, Mac1, and Mac2a, we observed the increase in p53, indicating the fully functional p53. In the remaining cell lines, P53 mutation analysis identified a homozygous nonsense mutation (R196Stop in Hut-78) and a homozygous missense mutation (G245S in SeAx). In MyLa2000, Mac1, and Mac2a carrying wild-type P53, nutlin-3a induced apoptosis and senescence demonstrated by permanent G0/G1 cell-cycle block and expression of the senescence-associated Β-galactosidase. This effect was abolished in cells in which p53 was silenced by small interfering RNA. S{\'e}zary cells lack functional p53 and were resistant to nutlin-3a. However, nutlin-3a potentiated the efficacy of conventional chemotherapeutics not only in cells with intact p53 but also in Hut-78, SeAx, and S{\'e}zary cells. Thus, targeting p53 by nutlin-3a may constitute a therapeutic approach in CTCL because of increased apoptosis and senescence of tumor cells.",

author = "Valentina Manf{\'e} and Biskup, {Edyta Urszula} and Peter Johansen and Kamstrup, {Maria R{\o}rb{\ae}k} and Krejsgaard, {Thorbj{\o}rn Frej} and Niels Morling and Wulf, {Hans Chr.} and Robert Gniadecki",

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T1 - MDM2 inhibitor nutlin-3a induces apoptosis and senescence in cutaneous T-cell lymphoma: Role of p53

AU - Manfé, Valentina

AU - Biskup, Edyta Urszula

AU - Johansen, Peter

AU - Kamstrup, Maria Rørbæk

AU - Krejsgaard, Thorbjørn Frej

AU - Morling, Niels

AU - Wulf, Hans Chr.

AU - Gniadecki, Robert

PY - 2012/5

Y1 - 2012/5

N2 - P53 is rarely mutated in cutaneous T-cell lymphoma (CTCL) and is therefore a promising target for innovative therapeutic approaches. Nutlin-3a is an inhibitor of MDM2 (human homolog of murine double minute 2), which disrupts its interaction with p53, leading to the stabilization and activation of p53. To investigate the potential therapeutic use of nutlin-3a in CTCL, we screened CTCL lines Hut-78, SeAx, MyLa2000, Mac1, and Mac2a by measuring p53 levels after nutlin-3a treatment. In MyLa2000, Mac1, and Mac2a, we observed the increase in p53, indicating the fully functional p53. In the remaining cell lines, P53 mutation analysis identified a homozygous nonsense mutation (R196Stop in Hut-78) and a homozygous missense mutation (G245S in SeAx). In MyLa2000, Mac1, and Mac2a carrying wild-type P53, nutlin-3a induced apoptosis and senescence demonstrated by permanent G0/G1 cell-cycle block and expression of the senescence-associated Β-galactosidase. This effect was abolished in cells in which p53 was silenced by small interfering RNA. Sézary cells lack functional p53 and were resistant to nutlin-3a. However, nutlin-3a potentiated the efficacy of conventional chemotherapeutics not only in cells with intact p53 but also in Hut-78, SeAx, and Sézary cells. Thus, targeting p53 by nutlin-3a may constitute a therapeutic approach in CTCL because of increased apoptosis and senescence of tumor cells.

AB - P53 is rarely mutated in cutaneous T-cell lymphoma (CTCL) and is therefore a promising target for innovative therapeutic approaches. Nutlin-3a is an inhibitor of MDM2 (human homolog of murine double minute 2), which disrupts its interaction with p53, leading to the stabilization and activation of p53. To investigate the potential therapeutic use of nutlin-3a in CTCL, we screened CTCL lines Hut-78, SeAx, MyLa2000, Mac1, and Mac2a by measuring p53 levels after nutlin-3a treatment. In MyLa2000, Mac1, and Mac2a, we observed the increase in p53, indicating the fully functional p53. In the remaining cell lines, P53 mutation analysis identified a homozygous nonsense mutation (R196Stop in Hut-78) and a homozygous missense mutation (G245S in SeAx). In MyLa2000, Mac1, and Mac2a carrying wild-type P53, nutlin-3a induced apoptosis and senescence demonstrated by permanent G0/G1 cell-cycle block and expression of the senescence-associated Β-galactosidase. This effect was abolished in cells in which p53 was silenced by small interfering RNA. Sézary cells lack functional p53 and were resistant to nutlin-3a. However, nutlin-3a potentiated the efficacy of conventional chemotherapeutics not only in cells with intact p53 but also in Hut-78, SeAx, and Sézary cells. Thus, targeting p53 by nutlin-3a may constitute a therapeutic approach in CTCL because of increased apoptosis and senescence of tumor cells.

U2 - 10.1038/jid.2012.10

DO - 10.1038/jid.2012.10

M3 - Journal article

C2 - 22377766

SN - 0022-202X

VL - 132

SP - 1487

EP - 1496

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

ER -

MDM2 inhibitor nutlin-3a induces apoptosis and senescence in cutaneous T-cell lymphoma: Role of p53

Abstract

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