ArticleThe Journal of biological chemistry2012
Proapoptotic protein Smac mediates apoptosis in cisplatin-resistant ovarian cancer cells when treated with the anti-tumor agent AT101.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 49 citations in OpenAlex.
- The correlation between Smac, IAPs and mitochondrial apoptosis, muscle tenderness during postmortem aging of Oula Tibetan sheep meat.Food chemistry: X · 2024Article
- Teriflunomide/leflunomide synergize with chemotherapeutics by decreasing mitochondrial fragmentation via DRP1 in SCLC.iScience · 2024Article
- Endoplasmic reticulum stress-induced release and binding of calreticulin from human ovarian cancer cells.Cancer immunology, immunotherapy : CII · 2022Article
- Effects of trans-(±)-kusunokinin on chemosensitive and chemoresistant ovarian cancer cells.Oncology letters · 2022Article
- The SMAC mimetic AT-101 exhibits anti-tumor and anti-metastasis activity in lung adenocarcinoma cells by the IAPs/ caspase-dependent apoptosis and p65-NFƙB cross-talk.Iranian journal of basic medical sciences · 2021Article
- The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells in vitro.Archives of toxicology · 2021Article
- Bcl‑2 family: Novel insight into individualized therapy for ovarian cancer (Review).International journal of molecular medicine · 2020Review
- Oridonin enhances the anti-tumor activity of gemcitabine towards pancreatic cancer by stimulating Bax- and Smac-dependent apoptosis.Translational cancer research · 2020Article
- The regulatory role of HIF-1 in tubular epithelial cells in response to kidney injury.Histology and histopathology · 2020Review
- Stretching magnitude-dependent inactivation of AKT by ROS led to enhanced p53 mitochondrial translocation and myoblast apoptosis.Molecular biology of the cell · 2019Article
- Study on the expression of p53 and MMP-2 in patients with lung cancer after interventional therapy.Oncology letters · 2018Article
- ARD1 contributes to IKKβ-mediated breast cancer tumorigenesis.Cell death & disease · 2018Article
- Article
- The pan-Bcl2 Inhibitor AT101 Activates the Intrinsic Apoptotic Pathway and Causes DNA Damage in Acute Myeloid Leukemia Stem-Like Cells.Targeted oncology · 2017Article
- Relationship of the expression levels of XIAP and p53 genes in hepatocellular carcinoma and the prognosis of patients.Oncology letters · 2017Article
- Mcl-1 expression and JNK activation induces a threshold for apoptosis in Bcl-xL-overexpressing hematopoietic cells.Oncotarget · 2017Article
- BH3 mimetics suppress CXCL12 expression in human malignant peripheral nerve sheath tumor cells.Oncotarget · 2017Article
- Tetramethylpyrazine Protects against Early Brain Injury after Experimental Subarachnoid Hemorrhage by Affecting Mitochondrial-Dependent Caspase-3 Apoptotic Pathway.Evidence-based complementary and alternative medicine : eCAM · 2017Article
- Theaflavin-3, 3'-digallate induces apoptosis and G2 cell cycle arrest through the Akt/MDM2/p53 pathway in cisplatin-resistant ovarian cancer A2780/CP70 cells.International journal of oncology · 2016Article
- Caspase-3 feedback loop enhances Bid-induced AIF/endoG and Bak activation in Bax and p53-independent manner.Cell death & disease · 2015Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chemoresistance of ovarian cancer has been previously attributed to the expression and activation of Bcl-2 family proteins. BH3-mimetic molecules possessing potential anticancer activity are able to inhibit antiapoptotic Bcl-2 family proteins. AT101 (R-(-)-gossypol), a natural BH3-mimetic molecule, has shown anti-tumor activity as a single agent and in combination with standard anticancer therapies in a variety of tumor models. Here, we report the effect of AT101 on apoptosis in cisplatin-resistant ovarian cancer cells and identify the major molecular events that determine sensitivity. AT101 induced cell apoptosis by activating Bax through a conformational change, translocation, and oligomerization. The inhibition of Bax expression only partially prevented caspase-3 cleavage. However, the gene silencing of Bax had no effect on mitochondrial Smac release. Further experiments demonstrated that Smac reduction inhibited caspase-3 activation and attenuated cell apoptosis. More importantly, the inhibition of Smac or overexpression of XIAP attenuated Bax activation in ovarian cells. Furthermore, our data indicate that the Akt-p53 pathway is involved in the regulation of Smac release. Taken together, our data demonstrate the role of Smac and the molecular mechanisms of AT101-induced apoptosis of chemoresistant ovarian cancer cells. Our findings suggest that AT101 not only triggers Bax activation but also induces mitochondrial Smac release. Activated Smac can enhance Bax-mediated cellular apoptosis. Therefore, Smac mediates Bax activation to determine the threshold for overcoming cisplatin resistance in ovarian cancer cells.
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