Search results for "Mcl-1"

Mcl-1 targeting could be an intriguing perspective to cure cancer

2018

The Bcl-2 family, which plays important roles in controlling cancer development, is divided into antiapoptotic and proapoptotic members. The change in the balance between these members governs the life and death of the cells. Mcl-1 is an antiapoptotic member of this family and its distribution in normal and cancerous tissues strongly differs from that of Bcl-2. In human cancers, where upregulation of antiapoptotic proteins is common, Mcl-1 expression is regulated independent of Bcl-2 and its inhibition promotes senescence, a major barrier to tumorigenesis. Cancer chemotherapy determines various kinds of responses, such as senescence and autophagy; however, the ideal response to chemotherapy…

Mcl-1 and Bok transmembrane domains : Unexpected players in the modulation of apoptosis

2020

The Bcl-2 protein family comprises both proand antiapoptotic members that control the permeabilization of the mitochondrial outer membrane, a crucial step in the modulation of apoptosis. Recent research has demonstrated that the carboxyl-terminal transmembrane domain (TMD) of some Bcl-2 protein family mem-bers can modulate apoptosis; however, the transmembrane interactome of the antiapoptotic protein Mcl-1 remains largely unexplored. Here, we demonstrate that the Mcl-1 TMD forms homooligomers in the mitochondrial membrane, competes with full-length Mcl-1 protein with regards to its antiapoptotic function, and induces cell death in a Bok-dependent manner. While the Bok TMD oligomers locate p…

EFFECTS OF MCL-1 INHIBITION ON FOCAL ADHESION DYNAMICS IN BREAST CANCER MDA-MB-231 CELLS 

BCL-XL inhibition induces an FGFR4-mediated rescue response in colorectal cancer

2022

The heterogeneous therapy response observed in colorectal cancer is in part due to cancer stem cells (CSCs) that resist chemotherapeutic insults. The anti-apoptotic protein BCL-XL plays a critical role in protecting CSCs from cell death, where its inhibition with high doses of BH3 mimetics can induce apoptosis. Here, we screen a compound library for synergy with low-dose BCL-XL inhibitor A-1155463 to identify pathways that regulate sensitivity to BCL-XL inhibition and reveal that fibroblast growth factor receptor (FGFR)4 inhibition effectively sensitizes to A-1155463 both in vitro and in vivo. Mechanistically, we identify a rescue response that is activated upon BCL-XL inhibition and leads …

A‐1210477 sensitizes TRAIL-induced apoptosis in MDA-MB-231 Triple Negative Breast Cancer cells.

2018

Triple negative breast cancer (TNBC) is a form of BC characterized by high aggressiveness, therapy resistance, short time to relapse, poor prognosis. The presence of Cancer Stem Cells (CSCs) could be responsible for TNBC resistance to therapy, recurrence and metastasis, and might explain the difficult of its eradication. Mcl-1 is one of the key regulators of CSCs self-renewal and its expression can limit the efficacy of antitumorigenic agents as TRAIL, a selective anticancer agent but with limited effects against some cancer cell lines. Here we investigated the expression profiles of Mcl-1 in TNBC tissue and cell lines. We also evaluated the effect of A-1210477, a selective Mcl-1 inhibitor,…

Mécanismes de résistance à l'apoptose induite par TRAIL dans les cellules cancéreuses : restauration de la sensibiltié à TRAIL par la chimiothérapie …

2010

The TNF-family member TRAIL (TNF-related apoptosis inducing ligand) is a cytokine involved in immune anti-tumour surveillance. TRAIL is one of the most promising agents currently under investigation, as it exhibits efficient anti-cancer cytotoxicity with limited side effects on healthy cells. The problem in current cancer therapy is that some cancer cells are already resistant, or can become resistant to TRAIL-induced cell death. The aim of my thesis was to study the mechanisms of resistance to TRAIL, and to find a way to bypass it. First, we were interested in the TRAIL-R4 antagonistic receptor, which is known to bind TRAIL without inducing a death signal. We have demonstrated for the firs…

Targeting HSP90 with the small molecule inhibitor AUY922 (luminespib) as a treatment strategy against hepatocellular carcinoma

2018

Hepatocellular carcinoma (HCC) is a highly malignant tumor that responds very poorly to existing therapies, most probably due to its extraordinary inter- and intra-tumor molecular heterogeneity. The modest therapeutic response to molecular targeted agents underlines the need for new therapeutic approaches for HCC. In our study, we took advantage of well-characterized human HCC cell lines, differing in transcriptomic subtypes, DNA mutation and amplification alterations, reflecting the heterogeneity of primary HCCs, to provide a preclinical evaluation of the specific heat shock protein 90 (HSP90) inhibitor AUY922 (luminespib). Indeed, HSP90 is highly expressed in different tumor types, but it…