Bortezomib Sensitizes Human Renal Cell Carcinomas to TRAIL Apoptosis through Increased Activation of Caspase-8 in the Death-Inducing Signaling Complex

Brooks, Alan D.; Jacobsen, Kristen M.; Li, Wenqing; Shanker, Anil; Sayers, Thomas J.

doi:10.1158/1541-7786.mcr-10-0022

Cited by 59 publications

(56 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Death receptor-mediated (extrinsic) apoptosis represents one of the most important cytotoxic pathways activated by anticancer agents (11,27,(41)(42)(43)(44). In this study, we demonstrated, to our knowledge for the first time, that neddylation inhibition with MLN4924 induces DR5-mediated apoptosis in ESCC cells.…”

Section: Discussionmentioning

confidence: 51%

Neddylation Inhibition Activates the Extrinsic Apoptosis Pathway through ATF4–CHOP–DR5 Axis in Human Esophageal Cancer Cells

Chen

Liang

et al. 2016

Clinical Cancer Research

109

102

View full text Add to dashboard Cite

Purpose: Targeting the protein neddylation pathway has become an attractive anticancer strategy; however, the role of death receptor-mediated extrinsic apoptosis during treatment remained to be determined.Experimental Design: The activation of extrinsic apoptosis and its role in MLN4924 treatment of human esophageal squamous cell carcinoma (ESCC) were evaluated both in vitro and in vivo. The expression of the components of extrinsic apoptotic pathway was determined by immunoblotting analysis and downregulated by siRNA silencing for mechanistic studies.Results: Pharmaceutical or genetic inactivation of neddylation pathway induced death receptor 5 (DR5)-mediated apoptosis and led to the suppression of ESCC in murine models. Mechanistically, neddylation inhibition stabilized activating transcription factor 4 (ATF4), a Cullin-Ring E3 ubiquitin ligases (CRL) substrate. Transcription factor CHOP was subsequently transactivated by ATF4 and further induced the expression of DR5 to activate caspase-8 and induce extrinsic apoptosis. Moreover, the entire neddylation pathway was hyperactivated in ESCC and was negatively associated with patient overall survival.Conclusions: Our findings highlight a critical role of ATF4-CHOP-DR5 axis-mediated extrinsic apoptosis in neddylationtargeted cancer therapy and support the clinical investigation of neddylation inhibitors (e.g., MLN4924) for the treatment of ESCC, a currently treatment-resistant disease with neddylation hyperactivation.

show abstract

Section: Discussionmentioning

confidence: 51%

Neddylation Inhibition Activates the Extrinsic Apoptosis Pathway through ATF4–CHOP–DR5 Axis in Human Esophageal Cancer Cells

Chen

Liang

et al. 2016

Clinical Cancer Research

109

102

View full text Add to dashboard Cite

show abstract

“…Sorafenib is approved for the treatment of advanced renal cell carcinomas (RCCs) (32)(33)(34)(35), a cancer entity that frequently shows resistance not only to conventional radio-and chemotherapy but also to experimental therapy with TRAIL (22). Here we show that sorafenib overcomes the TRAIL resistance of various RCC cell lines.…”

Section: Renal Cell Carcinoma (Rcc) Is Polyresistant To Chemo-and Radmentioning

confidence: 83%

“…Strategies to overcome resistance to TRAIL-induced apoptosis comprise combinations with DNA-damaging therapies, including the use of chemotherapeutic drugs (19) and irradiation (20), or the inhibition of prosurvival signaling, e.g. the nuclear factor B (NF-B) pathway (21), inhibition of the proteasome (22,23), or inhibition of histone deacetylases (24), all of which have been shown to sensitize tumor cells for TRAIL. In addition, BH3 mimetics, small molecules like ABT-737 or Obatoclax may potentiate TRAIL-mediated apoptosis through binding to the hydrophobic groove at the surface of antiapoptotic Bcl-2 proteins, thereby blocking their prosurvival function (25,26).…”

Section: Renal Cell Carcinoma (Rcc) Is Polyresistant To Chemo-and Radmentioning

confidence: 99%

Bax/Bak-independent mitochondrial depolarization and reactive oxygen species induction by sorafenib overcome resistance to apoptosis in renal cell carcinoma

Gillissen

Richter

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Eric R. FearonRenal cell carcinoma (RCC) is polyresistant to chemo-and radiotherapy and biologicals, including TNF-related apoptosisinducing ligand (TRAIL). Sorafenib, a multikinase inhibitor approved for the treatment of RCC, has been shown to sensitize cancer cells to TRAIL-induced apoptosis, in particular by downregulation of the Bak-inhibitory Bcl-2 family protein Mcl-1. Here we demonstrate that sorafenib overcomes TRAIL resistance in RCC by a mechanism that does not rely on Mcl-1 downregulation. Instead, sorafenib induces rapid dissipation of the mitochondrial membrane potential (⌬⌿ m ) that is accompanied by the accumulation of reactive oxygen species (ROS). Loss of ⌬⌿ m and ROS production induced by sorafenib are independent of caspase activities and do not depend on the presence of the proapoptotic Bcl-2 family proteins Bax or Bak, indicating that both events are functionally upstream of the mitochondrial apoptosis signaling cascade. More intriguingly, we find that it is sorafenib-induced ROS accumulation that enables TRAIL to activate caspase-8 in RCC. This leads to apoptosis that involves activation of an amplification loop via the mitochondrial apoptosis pathway. Thus, our mechanistic data indicate that sorafenib bypasses central resistance mechanisms through a direct induction of ⌬⌿ m breakdown and ROS production. Activation of this pathway might represent a useful strategy to overcome the cell-inherent resistance to cancer therapeutics, including TRAIL, in multiresistant cancers such as RCC.Apoptotic cell death induced by the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) 2 plays an important role in immune surveillance and is a major immune defense mechanism against tumor cells. Consequently, the use of TRAIL, which preferentially kills cancer cells while sparing non-cancerous tissue, is a promising concept in anticancer therapy. Recombinant TRAIL and agonistic antibodies against the TRAIL receptors are therefore tested in clinical phase I and II studies (1-3).Binding of TRAIL to the death receptors DR4 (TRAIL-R1) and DR5 (TRAIL-R2) initiates receptor oligomerization and, via the adaptor protein Fas-associated protein with death domain (FADD), recruitment of the initiator caspase-8 to the death domain of the activated receptor (4, 5). Formation of this activation platform, the so-called death-inducing signaling complex, results in autocatalytic activation of caspase-8. In type I cells, active caspase-8 triggers, via direct proteolytic processing of caspase-3, a caspase cascade to induce apoptotic cell death. In type II cells, however, the E3-ligase X-linked inhibitor of apoptosis protein (XIAP) prevents accumulation of active caspase-3 by marking it for proteasomal degradation (6). Therefore, in type II cells, efficient caspase-3 activation upon death receptor signaling requires amplification via the mitochondrial apoptosis pathway. Activation of the mitochondrial pathway is achieved by mitochondrial outer membrane permeabilization (MOMP) (7). Upon MOMP, the ...

show abstract

“…However, the molecular mechanisms underlying the sensitizing effect of bortezomib seem to be complicated and may be specific to cancer types. In certain cancer types, sensitization to TRAIL resistance has been reported to be through proteasome inhibition, including upregulation of TRAIL receptors (34,38), activation of both extrinsic and intrinsic apoptosis pathways (39,40), and probably, many other multiple molecular machineries. For example, Hetschko and colleagues (34) showed that the proteasome inhibitors MG132, via enhancement of transcription and surface expression of DR5, potentiates TRAIL sensitivity and reactivates apoptosis in TRAIL-resistant high-grade gliomas.…”

Section: Discussionmentioning

confidence: 99%

Bortezomib Sensitizes HCC Cells to CS-1008, an Antihuman Death Receptor 5 Antibody, through the Inhibition of CIP2A

Chen

Liu

et al. 2011

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Previously, we have shown that bortezomib overcame TRAIL resistance in hepatocellular carcinoma (HCC) cells via the inhibition of Akt. Here, we report that bortezomib sensitizes these TRAIL-resistant cells, including Huh-7, Hep3B, and Sk-Hep1, to CS-1008, a humanized agonistic antihuman death receptor 5 antibody. Cancerous inhibitor of protein phosphatase 2A (CIP2A) mediated the sensitizing effect of bortezomib to CS-1008 through inhibiting protein phosphatase 2A (PP2A) activity. Combination treatment of bortezomib and CS-1008 downregulated CIP2A in a concentration-and time-dependent manner, and increased PP2A activity in HCC cells. Importantly, ectopic expression of CIP2A decreased Akt-related PP2A activity, indicating that CIP2A negatively regulates Akt-related PP2A activity in HCC cells. Moreover, silencing CIP2A by short interfering RNA enhanced CS-1008-induced apoptosis in HCC cells and ectopic expression of CIP2A in HCC cells abolished CS-1008-induced apoptosis, indicating that CIP2A plays an important role in the sensitizing effect of bortezomib to CS-1008. Finally, our in vivo data showed that CS-1008 and bortezomib combination treatment decreased tumor growth significantly. In conclusion, bortezomib sensitized HCC cells to CS-1008 through the inhibition of CIP2A. Mol Cancer Ther; 10(5); 892-901. Ó2011 AACR.

show abstract

Bortezomib Sensitizes Human Renal Cell Carcinomas to TRAIL Apoptosis through Increased Activation of Caspase-8 in the Death-Inducing Signaling Complex

Cited by 59 publications

References 35 publications

Neddylation Inhibition Activates the Extrinsic Apoptosis Pathway through ATF4–CHOP–DR5 Axis in Human Esophageal Cancer Cells

Neddylation Inhibition Activates the Extrinsic Apoptosis Pathway through ATF4–CHOP–DR5 Axis in Human Esophageal Cancer Cells

Bax/Bak-independent mitochondrial depolarization and reactive oxygen species induction by sorafenib overcome resistance to apoptosis in renal cell carcinoma

Bortezomib Sensitizes HCC Cells to CS-1008, an Antihuman Death Receptor 5 Antibody, through the Inhibition of CIP2A

Contact Info

Product

Resources

About