Bortezomib/proteasome inhibitor triggers both apoptosis and autophagy-dependent pathways in melanoma cells

Selimović, Denis; Porzig, Benjamin B.O.W.; El-Khattouti, Abdelouahid; Badura, Helene E.; Ahmad, Mutmid; Ghanjati, Foued; Santourlidis, Simeon; Haïkel, Youssef; Hassan, Mohamed

doi:10.1016/j.cellsig.2012.10.004

Cited by 131 publications

(140 citation statements)

References 46 publications

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“…An increasing number of studies show that autophagy removes these protein aggregates in the form of the aggresome to promote tumor cell survival (18,21,38,39). We found that Btz treatment induced the accumulation of ubiquitylated unfolded or misfolded proteins in SCC1 cells ( Fig.…”

Section: Btz Induces Both Autophagy and Apoptosis In Hnscc Cellsmentioning

confidence: 71%

Inhibition of HDAC6 Protein Enhances Bortezomib-induced Apoptosis in Head and Neck Squamous Cell Carcinoma (HNSCC) by Reducing Autophagy

Chang

Wang

2016

Journal of Biological Chemistry

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Chemoresistance is a major barrier to effective chemotherapy of solid tumors, including head and neck squamous cell carcinoma (HNSCC). Recently, autophagy, a highly conservative intracellular recycling system, has shown to be associated with chemoresistance in cancer cells. However, little is known about how autophagy plays a role in the development of chemoresistance in HNSCC and how autophagy is initiated when HNSCC cells undergo cytotoxic stress. Here, we report that autophagy was activated when HNSCC cells are treated with the proteasome inhibitor bortezomib, proposed as an alternative chemotherapeutic agent for both primary and cisplatin-resistant HNSCC cells. Ablation of histone deacetylase 6 (HDAC6) expression and its activity in HNSCC cells significantly inhibited autophagy induction by altering the phosphorylation status of mammalian target of rapamycin and enhanced the bortezomib cytotoxicity. Similarly, a combination regimen of bortezomib and the histone deacetylase inhibitor trichostatin A abolished HDAC6 activity and decreased autophagy induction while significantly enhancing bortezomib-induced apoptosis in HNSCC cells. These data uncover a novel molecular mechanism indicating that HDAC6 may serve as a critical causal link between autophagy, apoptosis, and the cell survival response in HNSCC. A combination regimen resulting in regression of autophagy improves chemotherapeutic efficacy, thereby providing a new strategy to overcome chemoresistance and to improve the treatment and survival of HNSCC patients.

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Section: Btz Induces Both Autophagy and Apoptosis In Hnscc Cellsmentioning

confidence: 71%

Inhibition of HDAC6 Protein Enhances Bortezomib-induced Apoptosis in Head and Neck Squamous Cell Carcinoma (HNSCC) by Reducing Autophagy

Chang

Wang

2016

Journal of Biological Chemistry

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“…The opening of this pore is accompanied by membrane potential (ΔΨ) collapse, calcium release, uptake of electrolytes and water, matrix swelling and ruptures of the mitochondrial outer membrane [42] . As a consequence, several factors are released into the cytosol including cytochrome c, apoptotic peptidase activating factor 1 (apaf-1), apoptosis-inducing factor (AIF) and caspase family members, which participate in apoptosis pathways [43][44][45] . Several agents, such as Ca 2+ , thiol oxidants, reactive oxygen species (ROS), and/or members of the Bcl -2 family of proteins can regulate cell death or survival by interference with MPTP opening [46][47][48] .…”

Section: Discussionmentioning

confidence: 99%

African eggplant (Solanum anguivi Lam.) fruit with bioactive polyphenolic compounds exerts in vitro antioxidant properties and inhibits Ca2+-induced mitochondrial swelling

Elekofehinti

Kamdem

Bolingon

et al. 2013

Asian Pacific Journal of Tropical Biomedicine

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“…Increased cellular levels of LC3-II and Beclin-1 proteins were found after bortezomib treatment of human glioblastoma U251 and U87 cells [74], melanoma cells [24], several cell lines of head and neck squamous cell carcinoma [76] and human osteosarcoma (HOS) cells [77]. In human colon cancer HCT116 cells and murine embryonic fibroblasts (MEFs) bortezomib increased www.fhc.viamedica.pl expression of LC3-II but did not lead to significant changes in Beclin-1 levels [75].…”

Section: Effects Of Different Classes Of Proteasome Inhibitors On Autmentioning

confidence: 99%

“…The compounds of this class have 1000 times greater potency than the analogues of peptide aldehydes and are highly specific in relation to proteasome. Peptide boronates reversibly inhibit the chymotrypsin-like activity, and dissociate slowly, thus providing a stable inhibition of proteasomal activity [19,20,23,24]. Of special clinical significance was the introduction into the cancer treatment the dipeptide boronic acid, bortezomib (PS-341), which reversibly and selectively inhibits the proteasome [19,21,25,26].…”

Section: Proteasome Inhibitorsmentioning

confidence: 99%

Crosstalk between autophagy and proteasome protein degradation systems: possible implications for cancer therapy

Wójcik

2014

Folia Histochem Cytobiol.

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Abstract:The Ubiquitin-Proteasomes System (UPS) and autophagy, two main intracellular protein degradation pathways within the eukaryotic cells which were originally regarded as rather independent, seem to be very closely related. Proteasome inhibitors, including the multipathway inhibitor bortezomib, are drawing increased attention for their therapeutic potential in the treatment of chronic inflammation and cancer, especially tumours with a high degree of malignancy. The over-activation of autophagy induces cell death and may act as a powerful tumour-suppressing mechanism. However, autophagy, serving as an important mechanism to generate nutrients in time of cellular stresses, may directly contribute to the survival of cells treated with proteasome inhibitors, and in consequence, may decrease the effectiveness of therapy. Results of studies performed on several cancer cell lines demonstrated synergy between proteasome inhibitors and autophagy inhibitors. Those results became the base for ongoing clinical trials investigating autophagy inhibition in combination with anti-cancer therapies, including bortezomib. This review provides summary of the latest data on the functioning of the UPS and the mechanisms of autophagy. The new insights describing the main pathways of autophagy activation in response to UPS inhibition related to: (i) Unfolded Protein Response, (ii) PI3K/Akt/mTOR pathway, and (iii) formation of aggresomes, are discussed. It is concluded that concomitant inhibition of the two main cellular protein degradation systems may provide new therapeutic modalities for cancer treatment.

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Bortezomib/proteasome inhibitor triggers both apoptosis and autophagy-dependent pathways in melanoma cells

Cited by 131 publications

References 46 publications

Inhibition of HDAC6 Protein Enhances Bortezomib-induced Apoptosis in Head and Neck Squamous Cell Carcinoma (HNSCC) by Reducing Autophagy

Inhibition of HDAC6 Protein Enhances Bortezomib-induced Apoptosis in Head and Neck Squamous Cell Carcinoma (HNSCC) by Reducing Autophagy

African eggplant (Solanum anguivi Lam.) fruit with bioactive polyphenolic compounds exerts in vitro antioxidant properties and inhibits Ca2+-induced mitochondrial swelling

Crosstalk between autophagy and proteasome protein degradation systems: possible implications for cancer therapy

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