Caveolin-1 negatively regulates TRAIL-induced apoptosis in human hepatocarcinoma cells

Zhao, Xiangxuan; Liu, Yong; i, Q; Wang, Xiaohui; Jin, Haijing; Mehrpour, Maryam; Chen, Quan

doi:10.1016/j.bbrc.2008.10.123

Cited by 31 publications

(15 citation statements)

References 27 publications

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“…These results suggest that increased TRAIL stress leads to HuR-mediated stabilization of transcripts corresponding to cell proliferation and anti-apoptotic processes (21, 42). For example, Cav1 is known to negatively regulate TRAIL-mediated apoptosis in hepatocellular carcinoma cells (43). Our results suggest that HuR targeting of Cav1 transcript at least partly contributes to the Cav1 -mediated counteraction of TRAIL-induced apoptosis.…”

Section: Resultsmentioning

confidence: 99%

HuR Contributes to TRAIL Resistance by Restricting Death Receptor 4 Expression in Pancreatic Cancer Cells

Romeo

Weber

Zarei

et al. 2016

Molecular Cancer Research

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Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers, in part, due to resistance to both conventional and targeted therapeutics. Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL) directly induces apoptosis through engagement of cell surface Death Receptors (DR4 and DR5), and has been explored as a molecular target for cancer treatment. Clinical trials with recombinant TRAIL and DR-targeting agents, however, have failed to show overall positive outcomes. Herein, we identify a novel TRAIL resistance mechanism governed by Hu antigen R (HuR, ELAV1), a stress-response protein abundant and functional in PDA cells. Exogenous HuR overexpression in TRAIL-sensitive PDA cell lines increases TRAIL resistance whereas silencing HuR in TRAIL-resistant PDA cells, by siRNA oligo-transfection, decreases TRAIL resistance. PDA cell exposure to soluble TRAIL induces HuR translocation from the nucleus to the cytoplasm. Furthermore, it is demonstrated that HuR interacts with the 3′-untranslated region (UTR) of DR4 mRNA. Pre-treatment of PDA cells with MS-444 (Novartis), an established small molecule inhibitor of HuR, substantially increased DR4 and DR5 cell surface levels and enhanced TRAIL sensitivity, further validating HuR’s role in affecting TRAIL apoptotic-resistance. NanoString™ analyses on the transcriptome of TRAIL-exposed PDA cells identified global HuR-mediated increases in anti-apoptotic processes. Taken together, these data extend HuR’s role as a key regulator of TRAIL-induced apoptosis. Implications Discovery of an important new HuR-mediated TRAIL resistance mechanism suggests that tumor-targeted HuR inhibition increases sensitivity to TRAIL-based therapeutics and supports their re-evaluation as an effective treatment for PDA patients.

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Section: Resultsmentioning

confidence: 99%

HuR Contributes to TRAIL Resistance by Restricting Death Receptor 4 Expression in Pancreatic Cancer Cells

Romeo

Weber

Zarei

et al. 2016

Molecular Cancer Research

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“…Death receptor agonists including Fas ligand, TNF␣, and TRAIL have all been reported to interact with or upregulate cav-1 (13,87,120). Cav-1 protein can be significantly induced by TNF␣ and TRAIL (13,87,120), whereas Fas has been suspected to interact with cav-1 upon stimulation by FasL (122,123). Elevated caspase activities and an increased active form of caspase-3 are known features of hyperoxia-induced lung cell apoptosis (43,44,122,50,51,78).…”

Section: Evidence For a Role Of Cav-1 In Pmn-mediated Inflamma-mentioning

confidence: 96%

“…Numerous studies have shown that cav-1 regulates apoptotic pathways at various stages of lung injury. Death receptor agonists including Fas ligand, TNF␣, and TRAIL have all been reported to interact with or upregulate cav-1 (13,87,120). Cav-1 protein can be significantly induced by TNF␣ and TRAIL (13,87,120), whereas Fas has been suspected to interact with cav-1 upon stimulation by FasL (122,123).…”

Section: Evidence For a Role Of Cav-1 In Pmn-mediated Inflamma-mentioning

confidence: 97%

Caveolin-1: a critical regulator of lung injury

Jin

Lee

Minshall

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

104

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Caveolin-1 (cav-1), a 22-kDa transmembrane scaffolding protein, is the principal structural component of caveolae. Cav-1 regulates critical cell functions including proliferation, apoptosis, cell differentiation, and transcytosis via diverse signaling pathways. Abundant in almost every cell type in the lung, including type I epithelial cells, endothelial cells, smooth muscle cells, fibroblasts, macrophages, and neutrophils, cav-1 plays a crucial role in the pathogenesis of acute lung injury (ALI). ALI and its severe form, acute respiratory distress syndrome (ARDS), are responsible for significant morbidity and mortality in intensive care units, despite improvement in ventilation strategies. The pathogenesis of ARDS is still poorly understood, and therapeutic options remain limited. In this article, we summarize recent data regarding the regulation and function of cav-1 in lung biology and pathology, in particular as it relates to ALI. We further discuss the potential molecular and cellular mechanisms by which cav-1 expression contributes to ALI. Investigating the cellular functions of cav-1 may provide new insights for understanding the pathogenesis of ALI and provide novel targets for therapeutic interventions in the future.

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“…Zhao et al 50 found that overexpression of caveolin-1 blocked TRAIL-induced apoptosis in human hepatocarcinoma cells. Thus, we can speculate that the reduced growth rate of our SW1222…”

Section: Cancer Therapymentioning

confidence: 99%

Vascular effects dominate solid tumor response to treatment with combretastatin A‐4‐phosphate

Lunt

Akerman

Hill

et al. 2011

Intl Journal of Cancer

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Vascular‐targeted therapeutics are increasingly used in the clinic. However, less is known about the direct response of tumor cells to these agents. We have developed a combretastatin‐A‐4‐phosphate (CA4P) resistant variant of SW1222 human colorectal carcinoma cells to examine the relative importance of vascular versus tumor cell targeting in the ultimate treatment response. SW1222Res cells were generated through exposure of wild‐type cells (SW1222WT) to increasing CA4P concentrations in vitro. Increased resistance was confirmed through analyses of cell viability, apoptosis and multidrug‐resistance (MDR) protein expression. In vivo, comparative studies examined tumor cell necrosis, apoptosis, vessel morphology and functional vascular end‐points following treatment with CA4P (single 100 mg/kg dose). Tumor response to repeated CA4P dosing (50 mg/kg/day, 5 days/week for 2 weeks) was examined through growth measurement, and ultimate tumor cell survival was studied by ex vivo clonogenic assay. In vitro, SW1222Res cells showed reduced CA4P sensitivity, enhanced MDR protein expression and a reduced apoptotic index. In vivo, CA4P induced significantly lower apoptotic cell death in SW1222Res versus SW1222WT tumors indicating maintenance of resistance characteristics. However, CA4P‐induced tumor necrosis was equivalent in both lines. Similarly, rapid CA4P‐mediated vessel disruption and blood flow shut‐down were observed in both lines. Cell surviving fraction was comparable in the two tumor types following single dose CA4P and SW1222Res tumors were at least as sensitive as SW1222WT tumors to repeated dosing. Despite tumor cell resistance to CA4P, SW1222Res response in vivo was not impaired, strongly supporting the view that vascular damage dominates the therapeutic response to this agent.

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Caveolin-1 negatively regulates TRAIL-induced apoptosis in human hepatocarcinoma cells

Cited by 31 publications

References 27 publications

HuR Contributes to TRAIL Resistance by Restricting Death Receptor 4 Expression in Pancreatic Cancer Cells

HuR Contributes to TRAIL Resistance by Restricting Death Receptor 4 Expression in Pancreatic Cancer Cells

Caveolin-1: a critical regulator of lung injury

Vascular effects dominate solid tumor response to treatment with combretastatin A‐4‐phosphate

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