Thapsigargin sensitizes human melanoma cells to TRAIL-induced apoptosis by up-regulation of TRAIL-R2 through the unfolded protein response

Chen, Li Hua; Jiang, Chen Chen; Kiejda, Kelly A.; Wang, Yu Fang; Thorne, Rick F.; Zhang, Xu Dong; Hersey, Peter

doi:10.1093/carcin/bgm173

Cited by 47 publications

(45 citation statements)

References 38 publications

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“…Accumulating evidence supports the notion that ER stressinducing agents induce up-regulation of DR5 in a wide spectrum of human cancers through various mechanisms (20,23,(25)(26)(27)(28). DR5 modulation may have potential therapeutic value if combined with TRAIL in a clinically relevant manner.…”

Section: Discussionmentioning

confidence: 85%

Modulation of CCAAT/Enhancer Binding Protein Homologous Protein (CHOP)-dependent DR5 Expression by Nelfinavir Sensitizes Glioblastoma Multiforme Cells to Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)

Tian

Alonso‐Basanta

et al. 2011

Journal of Biological Chemistry

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Human glioblastoma multiforme cells demonstrate varying levels of sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Endoplasmic reticulum (ER) stress has been shown to trigger cell death through apoptosis. We therefore pursued a strategy of integrating clinically relevant investigational agents that cooperate mechanistically through the regulation of ER stress and apoptosis pathways. Nelfinavir belongs to the protease inhibitor class of drugs currently used to treat patients with HIV and is in clinical trials as an anti-tumor agent. We found that Nelfinavir treatment led to ER stress-induced up-regulation of the DR5 receptor. This transactivation was mediated by the transcription factor CCAAT/enhancer binding protein homologous protein (CHOP). We also determined that ER stress-induced ATF4 up-regulation was responsible for modulation of CHOP. In contrast, DR4 receptor expression was unchanged by Nelfinavir treatment. Combining Nelfinavir with TRAIL led to a significantly enhanced level of apoptosis that was abrogated by siRNA silencing of DR5. We provide evidence that Nelfinavirinduced ER stress modulates DR5 expression in human glioblastoma multiforme cells and can enhance TRAIL efficacy. These studies provide a potential mechanistic rationale for the use of the Food and Drug Administration-approved agent Nelfinavir in combination with DR5 agonists to induce apoptosis in human malignancies.Malignant gliomas account for ϳ70% of the 22,500 new cases of malignant primary brain tumors that are diagnosed in adults in the United States each year (1). Glioblastoma multiforme is a high-grade, highly lethal, and frequent brain tumor in adults. Traditional treatments such as DNA damaging agents and radiotherapy have demonstrated modest effects on patient survival, likely because in part of an inherent high-level expression of anti-apoptotic proteins such as Bcl-2, Bcl-X L , and sFLIP (2, 3). Frequent gene amplification and overexpression of the death decoy receptor DcR3 have also been reported in glioblastoma (4). Therefore, new strategies to induce apoptosis may help to overcome therapeutic resistance and improve efficacy.Nelfinavir is an HIV protease inhibitor and has been used to treat HIV/AIDS patients for over a decade. Recently, several groups reported the anticancer activity of Nelfinavir in a wide range of human cancer cell lines and tumor xenografts. Nelfinavir induces ER 2 stress, the unfolded protein response, autophagy, apoptosis, and caspase-independent cell death in various cancer cells (5-9). Multiple mechanisms have been proposed to explain the anticancer activities of the drug, such as inhibition of AKT/protein kinase B (PKB) activation (10), the proteasome (9), or signal transducer and activator of transcription (STAT) 3 (11), and down-regulation of hypoxia-inducible factor 1␣ (HIF-1␣)/VEGF expression (8). However, the exact molecular mechanisms of Nelfinavir efficacy in human cancer cells remains unclear and may be cell type-specific. We currently have an...

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Section: Discussionmentioning

confidence: 85%

Modulation of CCAAT/Enhancer Binding Protein Homologous Protein (CHOP)-dependent DR5 Expression by Nelfinavir Sensitizes Glioblastoma Multiforme Cells to Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)

Tian

Alonso‐Basanta

et al. 2011

Journal of Biological Chemistry

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“…However, silencing of DR5, but not DR4, abrogated the effect of 2-14 on TRAIL-induced apoptosis in HT-29 and DLD-1. These data are not surprising because it is known that DR5 binds TRAIL with greater affinity than DR4 (5) and that, even in the absence of DR4, DR5 is sufficient to deliver TRAIL-induced apoptotic signals (27,40,41). DR5 expression can be positively regulated by the transcription factor PPAR-g (42), and by p53 and CHOP, 2 proteins that bind to and enhance DR5 promoter activity (43).…”

Section: Discussionmentioning

confidence: 90%

“…Therefore, we developed several derivatives of mesalamine and selected 2-14 as it was the more potent inhibitor of colon cancer cell growth (25). Because our previous study showed that treatment of colon cancer cell lines with 2-14 triggers endoplasmic reticulum stress (25), a phenomenon that has been involved in the regulation of the expression of various components of the TRAIL-driven apoptotic pathway (26,27), we hypothesized that 2-14 could restore the sensitivity of colon cancer cells to TRAIL. In this study, we assessed the in vitro and in vivo effect of 2-14 on TRAIL-induced colon cancer cell apoptosis.…”

Section: Introductionmentioning

confidence: 99%

2-Methoxy-5-Amino-N-Hydroxybenzamide Sensitizes Colon Cancer Cells to TRAIL-Induced Apoptosis by Regulating Death Receptor 5 and Survivin Expression

Stolfi

Caruso

Franzè

et al. 2011

Molecular Cancer Therapeutics

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TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis is a crucial event in the control of tumor growth. However, many cancer cells, including colon cancer cells, are resistant to TRAIL-driven cell death. We have recently shown that 2-methoxy-5-amino-N-hydroxybenzamide (herein termed 2-14), a novel derivative of mesalamine, induces endoplasmic reticulum stress in colon cancer cells. Because endoplasmic reticulum stress-induced signals regulate the expression of molecules involved in TRAIL-driven apoptosis, we examined whether 2-14 makes colon cancer cells sensitive to TRAIL. Colon cancer cells were cultured with 2-14 and/or TRAIL. Death receptor (DR) 4/DR5 were analyzed by real-time PCR and flow cytometry. TRAIL pathway-associated proteins and extracellular signal-regulated kinase (ERK) were assessed by Western blotting. The in vivo capability of 2-14 to sensitize colon cancer cells to TRAIL-induced apoptosis was evaluated in a syngenic colon cancer model in which CT26-derived grafts were induced in mice. 2-14 promoted ERK-dependent induction of DR5, thereby enhancing TRAIL-mediated caspase-8 activation and apoptosis. Analysis of TRAIL-related pro-and antiapoptotic factors and functional studies revealed that survivin is involved in the protection of colon cancer cells against TRAIL-driven apoptosis. Notably, 2-14 enhanced ubiquitination and proteasome-mediated degradation of survivin. These data were confirmed in a murine model of TRAIL-resistant colon cancer in which 2-14 upregulated DR5, reduced survivin expression, and synergized with TRAIL in inhibiting tumor growth. Similarly, intraperitoneal administration of 2-14 to mice upregulated DR5 and downregulated survivin in a model of colitis-associated colon cancer. These findings indicate that 2-14 acts as a sensitizer for TRAIL-induced apoptosis and suggest that 2-14 can be useful in the therapy for TRAIL-resistant colon cancer. Mol Cancer Ther; 10(10); 1969-81. Ó2011 AACR.

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“…These observations indicated that activation of caspase-4 was downstream of caspase-3. Activated caspase-3 is known to enhance activation of caspase-8 and -9 in a positive feedback fashion [37,38]. Caspase-3 was also reported to directly activate caspase-2 in TRAIL-induced apoptosis [8].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the results may have important implications in treatment of melanoma with TRAIL in that co-treatment with agents that facilitate the ER stress-induced apoptotic pathway could be expected to increase cell death induced by TRAIL. We have shown previously that high levels of ER stress-induced by TM or TG up-regulates the expression of TRAIL receptor-2 (TRAIL-R2) which are down-regulated in most melanoma [38,39]. These dual effects could be expected to enhance the effectiveness of TRAIL.…”

Section: Discussionmentioning

confidence: 99%

TRAIL-induced apoptosis of human melanoma cells involves activation of caspase-4

et al. 2010

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Although it is conventionally regarded as an inflammatory caspase, recent studies have shown that caspase-4 plays a role in induction of apoptosis by endoplasmic reticulum (ER) stress. We report here that activation of caspase-4 is also involved in induction of apoptosis by TNF-related apoptosis-inducing ligand (TRAIL) in human melanoma cells. Treatment with TRAIL resulted in activation of caspase-4. This appeared to be mediated by caspase-3, in that caspase-4 was activated later than caspase-8, -9, and -3, and that inhibition of caspase-3 blocked TRAIL-induced caspase-4 activation. Notably, TRAIL triggered ER stress in melanoma cells as shown by up-regulation of the GRP78 protein and the spliced form of XBP-1 mRNA. This seemed to be necessary for activation of caspase-4, as activation of caspase-3 by agents that did not trigger ER stress did not cause activation of caspase-4. Importantly, inhibition of caspase-4 also partially blocked caspase-3 activation, suggesting that activation of caspase-4 may be positive feed-back mechanism to further enhance caspase-3 activation. Collectively, these results show that activation of caspase-4 contributes to TRAIL-induced apoptosis and is associated with induction of ER stress by TRAIL in melanoma cells, and may have important implications for improving therapeutic efficacies of TRAIL in melanoma.

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Thapsigargin sensitizes human melanoma cells to TRAIL-induced apoptosis by up-regulation of TRAIL-R2 through the unfolded protein response

Cited by 47 publications

References 38 publications

Modulation of CCAAT/Enhancer Binding Protein Homologous Protein (CHOP)-dependent DR5 Expression by Nelfinavir Sensitizes Glioblastoma Multiforme Cells to Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)

Modulation of CCAAT/Enhancer Binding Protein Homologous Protein (CHOP)-dependent DR5 Expression by Nelfinavir Sensitizes Glioblastoma Multiforme Cells to Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)

2-Methoxy-5-Amino-N-Hydroxybenzamide Sensitizes Colon Cancer Cells to TRAIL-Induced Apoptosis by Regulating Death Receptor 5 and Survivin Expression

TRAIL-induced apoptosis of human melanoma cells involves activation of caspase-4

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