Role of Apollon in human melanoma resistance to antitumor agents that activate the intrinsic or the extrinsic apoptosis pathways

Elena Tassi, Marina Zanon, Claudia Vegetti, Alessandra Molla, Ilaria Bersani, Valentina Perotti, Marzia Pennati, Nadia Zaffaroni, Michele Milella, Soldano Ferrone, Carmelo Carlo-Stella, Alessandro M. Gianni, Roberta Mortarini, Andrea Anichini

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Purpose: To assess the role of Apollon in melanoma resistance to intrinsic and extrinsic pathways of apoptosis and to identify strategies to reduce its expression. Experimental Design: Apollon expression was assessed in melanoma cells in vitro and in vivo. Apollon modulation and melanoma apoptosis were evaluated by Western blot and/or flow cytometry in response to cytotoxic drugs, mitogen-activated protein/extracellular signal-regulated kinase (MEK)-, BRAFV600E-, and mTOR-specific inhibitors, TRAIL and anti-HLA class II monoclonal antibodies (mAb). Mitochondrial depolarization, caspase activation, apoptosis assays, and gene expression profiling were used to test effects of Apollon silencing, by siRNA, on melanoma response to antitumor agents. Results: Apollon was constitutively expressed by melanoma cells, in vitro and in vivo, and at higher levels than in benign melanocytic lesions. Melanoma apoptosis correlated significantly with Apollon protein downmodulation in response to cytotoxic drugs, MEK, or BRAFV600E-specific inhibitors. Combinatorial treatment with MEK and mTOR inhibitors and HLA class II ligation, by a specific mAb, promoted Apollon downmodulation and enhanced melanoma apoptosis. Apollon downmodulation induced by antitumor agents was caspase independent, but proteasome dependent. Knockdown of Apollon, by siRNA, triggered apoptosis and/or significantly enhanced melanoma cell death in response to cytotoxic drugs, MEK-and BRAFV600E-specific inhibitors, and soluble or membrane-bound TRAIL. Apollon silencing promoted mitochondrial depolarization and caspase-2, caspase-8, caspase-9, and caspase-3 activation in response to different antitumor agents and altered the profile of genes modulated by MEK or BRAFV600E-specific inhibitors. Conclusions: Targeting of Apollon may significantly improve melanoma cell death in response to antitumor agents that trigger the intrinsic or the extrinsic apoptosis pathways. 3316-27.

Original languageEnglish
Pages (from-to)3316-3327
Number of pages12
JournalClinical Cancer Research
Volume18
Issue number12
DOIs
Publication statusPublished - Jun 15 2012

Fingerprint

Antineoplastic Agents
Melanoma
Apoptosis
Mitogen-Activated Protein Kinase Kinases
Caspases
Small Interfering RNA
Cell Death
Monoclonal Antibodies
Caspase 2
Pharmaceutical Preparations
Caspase 9
Caspase 8
Extracellular Signal-Regulated MAP Kinases
Gene Expression Profiling
Proteasome Endopeptidase Complex
Mitogens
Caspase 3
Ligation
Flow Cytometry
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Role of Apollon in human melanoma resistance to antitumor agents that activate the intrinsic or the extrinsic apoptosis pathways. / Tassi, Elena; Zanon, Marina; Vegetti, Claudia; Molla, Alessandra; Bersani, Ilaria; Perotti, Valentina; Pennati, Marzia; Zaffaroni, Nadia; Milella, Michele; Ferrone, Soldano; Carlo-Stella, Carmelo; Gianni, Alessandro M.; Mortarini, Roberta; Anichini, Andrea.

In: Clinical Cancer Research, Vol. 18, No. 12, 15.06.2012, p. 3316-3327.

Research output: Contribution to journalArticle

@article{45c4792fdef34e25a2606e591916dd79,
title = "Role of Apollon in human melanoma resistance to antitumor agents that activate the intrinsic or the extrinsic apoptosis pathways",
abstract = "Purpose: To assess the role of Apollon in melanoma resistance to intrinsic and extrinsic pathways of apoptosis and to identify strategies to reduce its expression. Experimental Design: Apollon expression was assessed in melanoma cells in vitro and in vivo. Apollon modulation and melanoma apoptosis were evaluated by Western blot and/or flow cytometry in response to cytotoxic drugs, mitogen-activated protein/extracellular signal-regulated kinase (MEK)-, BRAFV600E-, and mTOR-specific inhibitors, TRAIL and anti-HLA class II monoclonal antibodies (mAb). Mitochondrial depolarization, caspase activation, apoptosis assays, and gene expression profiling were used to test effects of Apollon silencing, by siRNA, on melanoma response to antitumor agents. Results: Apollon was constitutively expressed by melanoma cells, in vitro and in vivo, and at higher levels than in benign melanocytic lesions. Melanoma apoptosis correlated significantly with Apollon protein downmodulation in response to cytotoxic drugs, MEK, or BRAFV600E-specific inhibitors. Combinatorial treatment with MEK and mTOR inhibitors and HLA class II ligation, by a specific mAb, promoted Apollon downmodulation and enhanced melanoma apoptosis. Apollon downmodulation induced by antitumor agents was caspase independent, but proteasome dependent. Knockdown of Apollon, by siRNA, triggered apoptosis and/or significantly enhanced melanoma cell death in response to cytotoxic drugs, MEK-and BRAFV600E-specific inhibitors, and soluble or membrane-bound TRAIL. Apollon silencing promoted mitochondrial depolarization and caspase-2, caspase-8, caspase-9, and caspase-3 activation in response to different antitumor agents and altered the profile of genes modulated by MEK or BRAFV600E-specific inhibitors. Conclusions: Targeting of Apollon may significantly improve melanoma cell death in response to antitumor agents that trigger the intrinsic or the extrinsic apoptosis pathways. 3316-27.",
author = "Elena Tassi and Marina Zanon and Claudia Vegetti and Alessandra Molla and Ilaria Bersani and Valentina Perotti and Marzia Pennati and Nadia Zaffaroni and Michele Milella and Soldano Ferrone and Carmelo Carlo-Stella and Gianni, {Alessandro M.} and Roberta Mortarini and Andrea Anichini",
year = "2012",
month = "6",
day = "15",
doi = "10.1158/1078-0432.CCR-11-2232",
language = "English",
volume = "18",
pages = "3316--3327",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "12",

}

TY - JOUR

T1 - Role of Apollon in human melanoma resistance to antitumor agents that activate the intrinsic or the extrinsic apoptosis pathways

AU - Tassi, Elena

AU - Zanon, Marina

AU - Vegetti, Claudia

AU - Molla, Alessandra

AU - Bersani, Ilaria

AU - Perotti, Valentina

AU - Pennati, Marzia

AU - Zaffaroni, Nadia

AU - Milella, Michele

AU - Ferrone, Soldano

AU - Carlo-Stella, Carmelo

AU - Gianni, Alessandro M.

AU - Mortarini, Roberta

AU - Anichini, Andrea

PY - 2012/6/15

Y1 - 2012/6/15

N2 - Purpose: To assess the role of Apollon in melanoma resistance to intrinsic and extrinsic pathways of apoptosis and to identify strategies to reduce its expression. Experimental Design: Apollon expression was assessed in melanoma cells in vitro and in vivo. Apollon modulation and melanoma apoptosis were evaluated by Western blot and/or flow cytometry in response to cytotoxic drugs, mitogen-activated protein/extracellular signal-regulated kinase (MEK)-, BRAFV600E-, and mTOR-specific inhibitors, TRAIL and anti-HLA class II monoclonal antibodies (mAb). Mitochondrial depolarization, caspase activation, apoptosis assays, and gene expression profiling were used to test effects of Apollon silencing, by siRNA, on melanoma response to antitumor agents. Results: Apollon was constitutively expressed by melanoma cells, in vitro and in vivo, and at higher levels than in benign melanocytic lesions. Melanoma apoptosis correlated significantly with Apollon protein downmodulation in response to cytotoxic drugs, MEK, or BRAFV600E-specific inhibitors. Combinatorial treatment with MEK and mTOR inhibitors and HLA class II ligation, by a specific mAb, promoted Apollon downmodulation and enhanced melanoma apoptosis. Apollon downmodulation induced by antitumor agents was caspase independent, but proteasome dependent. Knockdown of Apollon, by siRNA, triggered apoptosis and/or significantly enhanced melanoma cell death in response to cytotoxic drugs, MEK-and BRAFV600E-specific inhibitors, and soluble or membrane-bound TRAIL. Apollon silencing promoted mitochondrial depolarization and caspase-2, caspase-8, caspase-9, and caspase-3 activation in response to different antitumor agents and altered the profile of genes modulated by MEK or BRAFV600E-specific inhibitors. Conclusions: Targeting of Apollon may significantly improve melanoma cell death in response to antitumor agents that trigger the intrinsic or the extrinsic apoptosis pathways. 3316-27.

AB - Purpose: To assess the role of Apollon in melanoma resistance to intrinsic and extrinsic pathways of apoptosis and to identify strategies to reduce its expression. Experimental Design: Apollon expression was assessed in melanoma cells in vitro and in vivo. Apollon modulation and melanoma apoptosis were evaluated by Western blot and/or flow cytometry in response to cytotoxic drugs, mitogen-activated protein/extracellular signal-regulated kinase (MEK)-, BRAFV600E-, and mTOR-specific inhibitors, TRAIL and anti-HLA class II monoclonal antibodies (mAb). Mitochondrial depolarization, caspase activation, apoptosis assays, and gene expression profiling were used to test effects of Apollon silencing, by siRNA, on melanoma response to antitumor agents. Results: Apollon was constitutively expressed by melanoma cells, in vitro and in vivo, and at higher levels than in benign melanocytic lesions. Melanoma apoptosis correlated significantly with Apollon protein downmodulation in response to cytotoxic drugs, MEK, or BRAFV600E-specific inhibitors. Combinatorial treatment with MEK and mTOR inhibitors and HLA class II ligation, by a specific mAb, promoted Apollon downmodulation and enhanced melanoma apoptosis. Apollon downmodulation induced by antitumor agents was caspase independent, but proteasome dependent. Knockdown of Apollon, by siRNA, triggered apoptosis and/or significantly enhanced melanoma cell death in response to cytotoxic drugs, MEK-and BRAFV600E-specific inhibitors, and soluble or membrane-bound TRAIL. Apollon silencing promoted mitochondrial depolarization and caspase-2, caspase-8, caspase-9, and caspase-3 activation in response to different antitumor agents and altered the profile of genes modulated by MEK or BRAFV600E-specific inhibitors. Conclusions: Targeting of Apollon may significantly improve melanoma cell death in response to antitumor agents that trigger the intrinsic or the extrinsic apoptosis pathways. 3316-27.

UR - http://www.scopus.com/inward/record.url?scp=84862536510&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862536510&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-11-2232

DO - 10.1158/1078-0432.CCR-11-2232

M3 - Article

VL - 18

SP - 3316

EP - 3327

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 12

ER -