Abstract
| Lingua originale | English |
|---|---|
| pagine (da-a) | 18432-18447 |
| Numero di pagine | 16 |
| Rivista | Journal of Cellular Physiology |
| Volume | 234 |
| Stato di pubblicazione | Published - 2019 |
Fingerprint
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
}
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 -