Loss of MCL1 function sensitizes the MDA-MB-231 breast cancer cells to rh-TRAIL by increasing DR4 levels

Giovanni Pratelli, Riccardo Di Fiore, Anna De Blasio, Rosa Drago-Ferrante, Riccardo Di Fiore, Christian Saliba, Shawn Baldacchino, Giovanni Pratelli, Anna De Blasio, Renza Vento, Giovanni Tesoriere, Christian Scerri, Godfrey Grech, Rosa Drago Ferrante

Risultato della ricerca: Article

2 Citazioni (Scopus)

Abstract

Triple-negative breast cancer (TNBC) is a form of BC characterized by high aggressiveness and therapy resistance probably determined by cancer stem cells. MCL1 is an antiapoptotic Bcl-2 family member that could limit the efficacy of anticancer agents as recombinant human tumor necrosis factor related apoptosis-inducing ligand (rh-TRAIL). Here, we investigated MCL1 expression in TNBC tissues and cells. We found MCL1 differentially expressed (upregulated or downregulated) in TNBC tissues. Furthermore, in comparison to the human mammary epithelial cells, we found that MDA-MB-231 cells show similar messenger RNA levels but higher MCL1 protein levels, whereas it resulted downregulated in MDA-MB-436 and BT-20 cells. We evaluated the effects of rh-TRAIL and A-1210477, a selective MCL1 inhibitor, on cell viability and growth of MDA-MB-231 cells. We demonstrated that the drug combination reduced the cell growth and activated the apoptotic pathway. Similar effects were observed on three-dimensional cultures and tertiary mammospheres of MDA-MB-231 cells. In MDA-MB-231 cells, after MCL1 silencing, rh-TRAIL confined the cell population in the sub-G0/G1 phase and induced a drop in the mitochondrial transmembrane potential. To understand the molecular mechanism by which the loss of MCL1 function sensitizes the MDA-MB-231 cells to rh-TRAIL, we analyzed by real-time reverse transcription polymerase chain reaction, the expression of genes related to apoptosis, stemness, cell cycle, and those involved in epigenetic regulation. Interestingly, among the upregulated genes through MCL1 silencing or inhibition, there was TNFRSF10A (DR4). Moreover, MCL1 inhibition increased DR4 protein levels and its cell surface expression. Finally, we demonstrated MCL1-DR4 interaction and dissociation of this complex after A-1210477 treatment. Overall, our findings highlight the potential MCL1-roles in MDA-MB-231 cells and suggest that MCL1 targeting could be an effective strategy to overcome TNBC's rh-TRAIL resistance.
Lingua originaleEnglish
pagine (da-a)18432-18447
Numero di pagine16
RivistaJournal of Cellular Physiology
Volume234
Stato di pubblicazionePublished - 2019

Fingerprint

Cells
Apoptosis
Breast Neoplasms
Ligands
Triple Negative Breast Neoplasms
Genes
Tissue
Polymerase chain reaction
Cell growth
Drug Combinations
Transcription
Stem cells
Antineoplastic Agents
human TNF protein
Down-Regulation
Proteins
Cell Cycle Resting Phase
Neoplastic Stem Cells
Messenger RNA
G1 Phase

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cita questo

Loss of MCL1 function sensitizes the MDA-MB-231 breast cancer cells to rh-TRAIL by increasing DR4 levels. / Pratelli, Giovanni; Di Fiore, Riccardo; De Blasio, Anna; Drago-Ferrante, Rosa; Di Fiore, Riccardo; Saliba, Christian; Baldacchino, Shawn; Pratelli, Giovanni; De Blasio, Anna; Vento, Renza; Tesoriere, Giovanni; Scerri, Christian; Grech, Godfrey; Drago Ferrante, Rosa.

In: Journal of Cellular Physiology, Vol. 234, 2019, pag. 18432-18447.

Risultato della ricerca: Article

Pratelli, G, Di Fiore, R, De Blasio, A, Drago-Ferrante, R, Di Fiore, R, Saliba, C, Baldacchino, S, Pratelli, G, De Blasio, A, Vento, R, Tesoriere, G, Scerri, C, Grech, G & Drago Ferrante, R 2019, 'Loss of MCL1 function sensitizes the MDA-MB-231 breast cancer cells to rh-TRAIL by increasing DR4 levels', Journal of Cellular Physiology, vol. 234, pagg. 18432-18447.
Pratelli, Giovanni ; Di Fiore, Riccardo ; De Blasio, Anna ; Drago-Ferrante, Rosa ; Di Fiore, Riccardo ; Saliba, Christian ; Baldacchino, Shawn ; Pratelli, Giovanni ; De Blasio, Anna ; Vento, Renza ; Tesoriere, Giovanni ; Scerri, Christian ; Grech, Godfrey ; Drago Ferrante, Rosa. / Loss of MCL1 function sensitizes the MDA-MB-231 breast cancer cells to rh-TRAIL by increasing DR4 levels. In: Journal of Cellular Physiology. 2019 ; Vol. 234. pagg. 18432-18447.
@article{78f5b863d45b4a01a3efdd8226b63728,
title = "Loss of MCL1 function sensitizes the MDA-MB-231 breast cancer cells to rh-TRAIL by increasing DR4 levels",
abstract = "Triple-negative breast cancer (TNBC) is a form of BC characterized by high aggressiveness and therapy resistance probably determined by cancer stem cells. MCL1 is an antiapoptotic Bcl-2 family member that could limit the efficacy of anticancer agents as recombinant human tumor necrosis factor related apoptosis-inducing ligand (rh-TRAIL). Here, we investigated MCL1 expression in TNBC tissues and cells. We found MCL1 differentially expressed (upregulated or downregulated) in TNBC tissues. Furthermore, in comparison to the human mammary epithelial cells, we found that MDA-MB-231 cells show similar messenger RNA levels but higher MCL1 protein levels, whereas it resulted downregulated in MDA-MB-436 and BT-20 cells. We evaluated the effects of rh-TRAIL and A-1210477, a selective MCL1 inhibitor, on cell viability and growth of MDA-MB-231 cells. We demonstrated that the drug combination reduced the cell growth and activated the apoptotic pathway. Similar effects were observed on three-dimensional cultures and tertiary mammospheres of MDA-MB-231 cells. In MDA-MB-231 cells, after MCL1 silencing, rh-TRAIL confined the cell population in the sub-G0/G1 phase and induced a drop in the mitochondrial transmembrane potential. To understand the molecular mechanism by which the loss of MCL1 function sensitizes the MDA-MB-231 cells to rh-TRAIL, we analyzed by real-time reverse transcription polymerase chain reaction, the expression of genes related to apoptosis, stemness, cell cycle, and those involved in epigenetic regulation. Interestingly, among the upregulated genes through MCL1 silencing or inhibition, there was TNFRSF10A (DR4). Moreover, MCL1 inhibition increased DR4 protein levels and its cell surface expression. Finally, we demonstrated MCL1-DR4 interaction and dissociation of this complex after A-1210477 treatment. Overall, our findings highlight the potential MCL1-roles in MDA-MB-231 cells and suggest that MCL1 targeting could be an effective strategy to overcome TNBC's rh-TRAIL resistance.",
keywords = "DR4 receptor, MCL1, cancer stem cells, rh-TRAIL, triple-negative breast cancer",
author = "Giovanni Pratelli and {Di Fiore}, Riccardo and {De Blasio}, Anna and Rosa Drago-Ferrante and {Di Fiore}, Riccardo and Christian Saliba and Shawn Baldacchino and Giovanni Pratelli and {De Blasio}, Anna and Renza Vento and Giovanni Tesoriere and Christian Scerri and Godfrey Grech and {Drago Ferrante}, Rosa",
year = "2019",
language = "English",
volume = "234",
pages = "18432--18447",
journal = "Journal of Cellular Physiology",
issn = "0021-9541",
publisher = "Wiley-Liss Inc.",

}

TY - JOUR

T1 - Loss of MCL1 function sensitizes the MDA-MB-231 breast cancer cells to rh-TRAIL by increasing DR4 levels

AU - Pratelli, Giovanni

AU - Di Fiore, Riccardo

AU - De Blasio, Anna

AU - Drago-Ferrante, Rosa

AU - Di Fiore, Riccardo

AU - Saliba, Christian

AU - Baldacchino, Shawn

AU - Pratelli, Giovanni

AU - De Blasio, Anna

AU - Vento, Renza

AU - Tesoriere, Giovanni

AU - Scerri, Christian

AU - Grech, Godfrey

AU - Drago Ferrante, Rosa

PY - 2019

Y1 - 2019

N2 - Triple-negative breast cancer (TNBC) is a form of BC characterized by high aggressiveness and therapy resistance probably determined by cancer stem cells. MCL1 is an antiapoptotic Bcl-2 family member that could limit the efficacy of anticancer agents as recombinant human tumor necrosis factor related apoptosis-inducing ligand (rh-TRAIL). Here, we investigated MCL1 expression in TNBC tissues and cells. We found MCL1 differentially expressed (upregulated or downregulated) in TNBC tissues. Furthermore, in comparison to the human mammary epithelial cells, we found that MDA-MB-231 cells show similar messenger RNA levels but higher MCL1 protein levels, whereas it resulted downregulated in MDA-MB-436 and BT-20 cells. We evaluated the effects of rh-TRAIL and A-1210477, a selective MCL1 inhibitor, on cell viability and growth of MDA-MB-231 cells. We demonstrated that the drug combination reduced the cell growth and activated the apoptotic pathway. Similar effects were observed on three-dimensional cultures and tertiary mammospheres of MDA-MB-231 cells. In MDA-MB-231 cells, after MCL1 silencing, rh-TRAIL confined the cell population in the sub-G0/G1 phase and induced a drop in the mitochondrial transmembrane potential. To understand the molecular mechanism by which the loss of MCL1 function sensitizes the MDA-MB-231 cells to rh-TRAIL, we analyzed by real-time reverse transcription polymerase chain reaction, the expression of genes related to apoptosis, stemness, cell cycle, and those involved in epigenetic regulation. Interestingly, among the upregulated genes through MCL1 silencing or inhibition, there was TNFRSF10A (DR4). Moreover, MCL1 inhibition increased DR4 protein levels and its cell surface expression. Finally, we demonstrated MCL1-DR4 interaction and dissociation of this complex after A-1210477 treatment. Overall, our findings highlight the potential MCL1-roles in MDA-MB-231 cells and suggest that MCL1 targeting could be an effective strategy to overcome TNBC's rh-TRAIL resistance.

AB - Triple-negative breast cancer (TNBC) is a form of BC characterized by high aggressiveness and therapy resistance probably determined by cancer stem cells. MCL1 is an antiapoptotic Bcl-2 family member that could limit the efficacy of anticancer agents as recombinant human tumor necrosis factor related apoptosis-inducing ligand (rh-TRAIL). Here, we investigated MCL1 expression in TNBC tissues and cells. We found MCL1 differentially expressed (upregulated or downregulated) in TNBC tissues. Furthermore, in comparison to the human mammary epithelial cells, we found that MDA-MB-231 cells show similar messenger RNA levels but higher MCL1 protein levels, whereas it resulted downregulated in MDA-MB-436 and BT-20 cells. We evaluated the effects of rh-TRAIL and A-1210477, a selective MCL1 inhibitor, on cell viability and growth of MDA-MB-231 cells. We demonstrated that the drug combination reduced the cell growth and activated the apoptotic pathway. Similar effects were observed on three-dimensional cultures and tertiary mammospheres of MDA-MB-231 cells. In MDA-MB-231 cells, after MCL1 silencing, rh-TRAIL confined the cell population in the sub-G0/G1 phase and induced a drop in the mitochondrial transmembrane potential. To understand the molecular mechanism by which the loss of MCL1 function sensitizes the MDA-MB-231 cells to rh-TRAIL, we analyzed by real-time reverse transcription polymerase chain reaction, the expression of genes related to apoptosis, stemness, cell cycle, and those involved in epigenetic regulation. Interestingly, among the upregulated genes through MCL1 silencing or inhibition, there was TNFRSF10A (DR4). Moreover, MCL1 inhibition increased DR4 protein levels and its cell surface expression. Finally, we demonstrated MCL1-DR4 interaction and dissociation of this complex after A-1210477 treatment. Overall, our findings highlight the potential MCL1-roles in MDA-MB-231 cells and suggest that MCL1 targeting could be an effective strategy to overcome TNBC's rh-TRAIL resistance.

KW - DR4 receptor

KW - MCL1

KW - cancer stem cells

KW - rh-TRAIL

KW - triple-negative breast cancer

UR - http://hdl.handle.net/10447/363225

UR - http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1097-4652

M3 - Article

VL - 234

SP - 18432

EP - 18447

JO - Journal of Cellular Physiology

JF - Journal of Cellular Physiology

SN - 0021-9541

ER -