ArticleCell death & disease2013
Targeted therapy of the XIAP/proteasome pathway overcomes TRAIL-resistance in carcinoma by switching apoptosis signaling to a Bax/Bak-independent 'type I' mode.
Article in Cell death & disease, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 46 citations in OpenAlex.
- Curcumin enhances the effects of TRAIL in TRAIL-resistant non-small cell lung cancer cell lines.BMC complementary medicine and therapies · 2026Article
- b-AP15 enhances TRAIL-induced cell death in HNSCC via the induction of ROS/JNK/DR5 signalling.Cancer gene therapy · 2026Article
- Targeting the inhibitors of apoptosis proteins (IAPs) to combat drug resistance in cancers.Frontiers in pharmacology · 2025Review
- Inhibition of Cell Proliferation and Cell Viability by Sinecatechins in Cutaneous SCC Cells Is Related to an Imbalance of ROS and Loss of Mitochondrial Membrane Potential.Antioxidants (Basel, Switzerland) · 2022Article
- The non-peptidomimetic IAP antagonist ASTX660 sensitizes colorectal cancer cells for extrinsic apoptosis.FEBS open bio · 2021Article
- Review
- Targeting apoptosis in cancer therapy.Nature reviews. Clinical oncology · 2020Review
- An Investigation Into the Prognostic Significance of High Proteasome PSB7 Protein Expression in Colorectal Cancer.Frontiers in medicine · 2020Article
- Targeting bone morphogenetic protein receptor 2 sensitizes lung cancer cells to TRAIL by increasing cytosolic Smac/DIABLO and the downregulation of X-linked inhibitor of apoptosis protein.Cell communication and signaling : CCS · 2019Article
- Heterogeneous responses to low level death receptor activation are explained by random molecular assembly of the Caspase-8 activation platform.PLoS computational biology · 2019Article
- Mathematical Modeling Highlights the Complex Role of AKT in TRAIL-Induced Apoptosis of Colorectal Carcinoma Cells.iScience · 2019Article
- Targeting the BIR Domains of Inhibitor of Apoptosis (IAP) Proteins in Cancer Treatment.Computational and structural biotechnology journal · 2019Review
- The prodomain of caspase-3 regulates its own removal and caspase activation.Cell death discovery · 2019Article
- The SMAC mimetic LCL-161 displays antitumor activity in preclinical models of rituximab-resistant B-cell lymphoma.Blood advances · 2018Article
- Hypertonicity-enforced BCL-2 addiction unleashes the cytotoxic potential of death receptors.Oncogene · 2018Article
- Combined application of Embelin and tumor necrosis factor-related apoptosis-inducing ligand inhibits proliferation and invasion in osteosarcoma cells via caspase-induced apoptosis.Oncology letters · 2018Article
- Article
- MicroRNA-519a-3p mediates apoptosis resistance in breast cancer cells and their escape from recognition by natural killer cells.Cell death & disease · 2017Article
- Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs).Apoptosis : an international journal on programmed cell death · 2017Review
- Bax/Bak-independent mitochondrial depolarization and reactive oxygen species induction by sorafenib overcome resistance to apoptosis in renal cell carcinoma.The Journal of biological chemistry · 2017Article
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
TRAIL is a promising anticancer agent, capable of inducing apoptosis in a wide range of treatment-resistant tumor cells. In 'type II' cells, the death signal triggered by TRAIL requires amplification via the mitochondrial apoptosis pathway. Consequently, deregulation of the intrinsic apoptosis-signaling pathway, for example, by loss of Bax and Bak, confers TRAIL-resistance and limits its application. Here, we show that despite resistance of Bax/Bak double-deficient cells, TRAIL-treatment resulted in caspase-8 activation and complete processing of the caspase-3 proenzymes. However, active caspase-3 was degraded by the proteasome and not detectable unless the XIAP/proteasome pathway was inhibited. Direct or indirect inhibition of XIAP by RNAi, Mithramycin A or by the SMAC mimetic LBW-242 as well as inhibition of the proteasome by Bortezomib overcomes TRAIL-resistance of Bax/Bak double-deficient tumor cells. Moreover, activation and stabilization of caspase-3 becomes independent of mitochondrial death signaling, demonstrating that inhibition of the XIAP/proteasome pathway overcomes resistance by converting 'type II' to 'type I' cells. Our results further demonstrate that the E3 ubiquitin ligase XIAP is a gatekeeper critical for the 'type II' phenotype. Pharmacological manipulation of XIAP therefore is a promising strategy to sensitize cells for TRAIL and to overcome TRAIL-resistance in case of central defects in the intrinsic apoptosis-signaling pathway.
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