Non-canonical roles of caspase-8 in MDA-MB-231 breast cancer cell line

Risultato della ricerca: Other

Abstract

Caspase-8 (casp-8) is well known as an initiator caspase involved in cell death signalling, although its activity in many cancer cell types seems to work under non-apoptotic conditions. Moreover, in several types of cancer, casp-8 is only rarely mutated and often its expression is very elevated. Since cancer cell growth also depends on evasion of apoptosis, the upregulation of casp-8 in tumours may suggest one or more non-apoptotic roles (1). Here we report our recent studies carried out in MDA-MB-231 cells, derived from clinically aggressive forms of Triple-Negative Breast Cancer, where we have assessed the non-canonical roles of casp-8. Firstly, we evaluated casp-8 mRNA and protein levels in MDA-MB-231 cells, demonstrating that they were upregulated with respect to HMEC (normal Human Mammalian Epithelial Cells). Thereafter, to assess the role of casp-8, we silenced it by small interfering-RNA. Interestingly casp-8-knockdown, strongly decreased MDA-MB-231 cell growth by delaying G0/G1- to S-phase transition and increasing p21, p27 and hypophosphorylated/active form of pRb levels. No effects were evidenced on cell viability. To assess the metastatic capacity of MDA-MB-231 cells, the gene expression profiles of the relative markers after casp-8 knockdown were also measured. Surprisingly the expression of a number of genes and/or proteins such as VEGFA, C-MYC, CTNNB1, HMGA2, CXCR4, KLF4, VERSICAN V1 and MMP2 potently increased accompanied by migratory and metastatic capacities of cells, as shown by wound healing and matrigel assays. We suggest that among these genes, KLF4, a transcriptional factor with a dual role (activator and repressor), and responsible for p21 and p27 induction, could play critical roles (2). Casp-8 through KLF4 down-regulation, could manage the expression of critical proliferative and migratory/invasive genes. We suggest that these unusual roles played by casp-8 in MDA-MB-231 cells, should be better explored, in order to identify it as a molecular therapeutic target.References1. Stupack DG. Caspase-8 as a Therapeutic Target in Cancer. Cancer Lett 332:133–140, 2013.2. Tiwari N et al. Klf4 Is a Transcriptional Regulator of Genes Critical for EMT, Including Jnk1 (Mapk8). PLoS One 8, 2013.
Lingua originaleEnglish
Numero di pagine3
Stato di pubblicazionePublished - 2015

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Caspase 8
Breast Neoplasms
Cell Line
Neoplasms
Initiator Caspases
Versicans
Triple Negative Breast Neoplasms
Phase Transition
Regulator Genes
Growth
S Phase
Transcriptome
Wound Healing
Small Interfering RNA
Genes
Cell Survival
Proteins
Cell Death
Up-Regulation
Down-Regulation

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title = "Non-canonical roles of caspase-8 in MDA-MB-231 breast cancer cell line",
abstract = "Caspase-8 (casp-8) is well known as an initiator caspase involved in cell death signalling, although its activity in many cancer cell types seems to work under non-apoptotic conditions. Moreover, in several types of cancer, casp-8 is only rarely mutated and often its expression is very elevated. Since cancer cell growth also depends on evasion of apoptosis, the upregulation of casp-8 in tumours may suggest one or more non-apoptotic roles (1). Here we report our recent studies carried out in MDA-MB-231 cells, derived from clinically aggressive forms of Triple-Negative Breast Cancer, where we have assessed the non-canonical roles of casp-8. Firstly, we evaluated casp-8 mRNA and protein levels in MDA-MB-231 cells, demonstrating that they were upregulated with respect to HMEC (normal Human Mammalian Epithelial Cells). Thereafter, to assess the role of casp-8, we silenced it by small interfering-RNA. Interestingly casp-8-knockdown, strongly decreased MDA-MB-231 cell growth by delaying G0/G1- to S-phase transition and increasing p21, p27 and hypophosphorylated/active form of pRb levels. No effects were evidenced on cell viability. To assess the metastatic capacity of MDA-MB-231 cells, the gene expression profiles of the relative markers after casp-8 knockdown were also measured. Surprisingly the expression of a number of genes and/or proteins such as VEGFA, C-MYC, CTNNB1, HMGA2, CXCR4, KLF4, VERSICAN V1 and MMP2 potently increased accompanied by migratory and metastatic capacities of cells, as shown by wound healing and matrigel assays. We suggest that among these genes, KLF4, a transcriptional factor with a dual role (activator and repressor), and responsible for p21 and p27 induction, could play critical roles (2). Casp-8 through KLF4 down-regulation, could manage the expression of critical proliferative and migratory/invasive genes. We suggest that these unusual roles played by casp-8 in MDA-MB-231 cells, should be better explored, in order to identify it as a molecular therapeutic target.References1. Stupack DG. Caspase-8 as a Therapeutic Target in Cancer. Cancer Lett 332:133–140, 2013.2. Tiwari N et al. Klf4 Is a Transcriptional Regulator of Genes Critical for EMT, Including Jnk1 (Mapk8). PLoS One 8, 2013.",
keywords = "breast cancer, caspase-8, metastatic capacity",
author = "Daniela Carlisi and Mauro Montalbano and {De Blasio}, Anna and {Di Fiore}, Riccardo and Renza Vento and Marco Morreale",
year = "2015",
language = "English",

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TY - CONF

T1 - Non-canonical roles of caspase-8 in MDA-MB-231 breast cancer cell line

AU - Carlisi, Daniela

AU - Montalbano, Mauro

AU - De Blasio, Anna

AU - Di Fiore, Riccardo

AU - Vento, Renza

AU - Morreale, Marco

PY - 2015

Y1 - 2015

N2 - Caspase-8 (casp-8) is well known as an initiator caspase involved in cell death signalling, although its activity in many cancer cell types seems to work under non-apoptotic conditions. Moreover, in several types of cancer, casp-8 is only rarely mutated and often its expression is very elevated. Since cancer cell growth also depends on evasion of apoptosis, the upregulation of casp-8 in tumours may suggest one or more non-apoptotic roles (1). Here we report our recent studies carried out in MDA-MB-231 cells, derived from clinically aggressive forms of Triple-Negative Breast Cancer, where we have assessed the non-canonical roles of casp-8. Firstly, we evaluated casp-8 mRNA and protein levels in MDA-MB-231 cells, demonstrating that they were upregulated with respect to HMEC (normal Human Mammalian Epithelial Cells). Thereafter, to assess the role of casp-8, we silenced it by small interfering-RNA. Interestingly casp-8-knockdown, strongly decreased MDA-MB-231 cell growth by delaying G0/G1- to S-phase transition and increasing p21, p27 and hypophosphorylated/active form of pRb levels. No effects were evidenced on cell viability. To assess the metastatic capacity of MDA-MB-231 cells, the gene expression profiles of the relative markers after casp-8 knockdown were also measured. Surprisingly the expression of a number of genes and/or proteins such as VEGFA, C-MYC, CTNNB1, HMGA2, CXCR4, KLF4, VERSICAN V1 and MMP2 potently increased accompanied by migratory and metastatic capacities of cells, as shown by wound healing and matrigel assays. We suggest that among these genes, KLF4, a transcriptional factor with a dual role (activator and repressor), and responsible for p21 and p27 induction, could play critical roles (2). Casp-8 through KLF4 down-regulation, could manage the expression of critical proliferative and migratory/invasive genes. We suggest that these unusual roles played by casp-8 in MDA-MB-231 cells, should be better explored, in order to identify it as a molecular therapeutic target.References1. Stupack DG. Caspase-8 as a Therapeutic Target in Cancer. Cancer Lett 332:133–140, 2013.2. Tiwari N et al. Klf4 Is a Transcriptional Regulator of Genes Critical for EMT, Including Jnk1 (Mapk8). PLoS One 8, 2013.

AB - Caspase-8 (casp-8) is well known as an initiator caspase involved in cell death signalling, although its activity in many cancer cell types seems to work under non-apoptotic conditions. Moreover, in several types of cancer, casp-8 is only rarely mutated and often its expression is very elevated. Since cancer cell growth also depends on evasion of apoptosis, the upregulation of casp-8 in tumours may suggest one or more non-apoptotic roles (1). Here we report our recent studies carried out in MDA-MB-231 cells, derived from clinically aggressive forms of Triple-Negative Breast Cancer, where we have assessed the non-canonical roles of casp-8. Firstly, we evaluated casp-8 mRNA and protein levels in MDA-MB-231 cells, demonstrating that they were upregulated with respect to HMEC (normal Human Mammalian Epithelial Cells). Thereafter, to assess the role of casp-8, we silenced it by small interfering-RNA. Interestingly casp-8-knockdown, strongly decreased MDA-MB-231 cell growth by delaying G0/G1- to S-phase transition and increasing p21, p27 and hypophosphorylated/active form of pRb levels. No effects were evidenced on cell viability. To assess the metastatic capacity of MDA-MB-231 cells, the gene expression profiles of the relative markers after casp-8 knockdown were also measured. Surprisingly the expression of a number of genes and/or proteins such as VEGFA, C-MYC, CTNNB1, HMGA2, CXCR4, KLF4, VERSICAN V1 and MMP2 potently increased accompanied by migratory and metastatic capacities of cells, as shown by wound healing and matrigel assays. We suggest that among these genes, KLF4, a transcriptional factor with a dual role (activator and repressor), and responsible for p21 and p27 induction, could play critical roles (2). Casp-8 through KLF4 down-regulation, could manage the expression of critical proliferative and migratory/invasive genes. We suggest that these unusual roles played by casp-8 in MDA-MB-231 cells, should be better explored, in order to identify it as a molecular therapeutic target.References1. Stupack DG. Caspase-8 as a Therapeutic Target in Cancer. Cancer Lett 332:133–140, 2013.2. Tiwari N et al. Klf4 Is a Transcriptional Regulator of Genes Critical for EMT, Including Jnk1 (Mapk8). PLoS One 8, 2013.

KW - breast cancer

KW - caspase-8

KW - metastatic capacity

UR - http://hdl.handle.net/10447/234931

UR - https://www.ibim.cnr.it/homebiotec

M3 - Other

ER -