Thapsigargin sensitizes human esophageal cancer to TRAIL-induced apoptosis via AMPK activation

Ma, Zhiqiang; Yang, Yang; Hu, Wei; Tian, Li; Zhu, Yongping; Han, Jing; Xin, Zhenlong; Wu, Guiling; Zhao, Jing; Li, Xiaofei; Yan, Xiaolong

doi:10.1038/srep35196

Cited by 44 publications

(36 citation statements)

References 73 publications

(91 reference statements)

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“…Interestingly, we found that the combination of lopinavir and ritonavir triggered TRAIL-receptor-mediated cytotoxicity and apoptosis by increasing the expression of the TRAIL receptor DR5. Several studies have shown that ER stress induction increased the expression of TRAIL receptors, thereby sensitizing cancer cells to TRAIL and inducing TRAIL-mediated apoptosis (11,14,38). Compatible with those studies, the increased DR5 expression we found was shown to be due to ER stress induced by the combination.…”

Section: Discussionsupporting

confidence: 75%

“…Previous studies demonstrated that ER stress induced AMPK expression in malignancies (11,12). Furthermore, AMPK is known to act against cancer by suppressing the mTOR pathway (13).…”

Section: Resultsmentioning

confidence: 98%

“…The combination increased the expression of a TRAIL receptor and thereby sensitized cancer cells to TRAIL. ER stress induction reportedly increases the expression of TRAIL receptors (11,14,15). Therefore, we next evaluated whether the combination increases the expression of a TRAIL receptor and thereby sensitizes the cancer cells to TRAIL.…”

Section: Resultsmentioning

confidence: 99%

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Lopinavir-Ritonavir Combination Induces Endoplasmic Reticulum Stress and Kills Urological Cancer Cells

et al. 2019

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Background/Aim: Induction of endoplasmic reticulum (ER) stress is a novel approach to cancer treatment. This study investigated the ability of the clinically feasible combination of the human immunodeficiency virus protease inhibitors lopinavir and ritonavir to induce ER stress killing urological cancer cells. Materials and Methods: Renal cancer cells (769-P, 786-O) and bladder cancer cells (UMUC-3, T-24) were used to investigate the ability of the combination to induce ER stress and its mechanism of action. Results: The combination inhibited the growth of both renal and bladder cancer cells synergistically by inducing ER stress. The combination-induced ER stress increased the expression of AMP-activated protein kinase and suppressed the mammalian target of rapamycin pathway. It also increased the expression of a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor and thereby sensitized the cancer cells to TRAIL. Conclusion: The combination of lopinavir and ritonavir acts against urological cancer cells by inducing ER stress synergistically. Materials and Methods Cell culture. Human renal cancer cells (769-P, 786-O) and human bladder cancer cells (UMUC-3, T-24) were purchased from the American Type Culture Collection (Rockville, MD, USA). The cells were cultured in either Roswell Park Memorial Institute Medium 1640 (769-P and 786-O cells), Minimum Essential Medium (UMUC-3 cells), or McCoy's 5A medium (T-24 cells) containing 10% fetal bovine serum and 1.0% penicillin/streptomycin (Invitrogen, Carlsbad, CA, USA) at 37˚C under 5% CO 2 in a humidified incubator. Reagents and antibodies. Ritonavir purchased from Toronto Research Chemicals (North York, ON, Canada) and lopinavir purchased from Selleck (Houston, TX, USA) were dissolved in dimethyl sulfoxide. Cycloheximide purchased from Enzo Life Sciences (Farmingdale, NY, USA) was dissolved in distilled water. Human recombinant TRAIL purchased from R&D Systems (Minneapolis, MN, USA) was dissolved in sterile phosphatebuffered saline (PBS) containing 0.1% bovine serum albumin. These solutions were stored at −80˚C or −20˚C until use. Primary antibodies for western blotting were used against the following: survivin and death receptor 5 (DR5) (Santa Cruz Biotechnology, Santa Cruz, CA, USA); cleaved poly(ADP-ribose) polymerase (PARP), S6 ribosomal protein, phosphorylated S6, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), and 5891 This article is freely accessible online.

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Section: Discussionsupporting

confidence: 75%

“…Previous studies demonstrated that ER stress induced AMPK expression in malignancies (11,12). Furthermore, AMPK is known to act against cancer by suppressing the mTOR pathway (13).…”

Section: Resultsmentioning

confidence: 98%

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Lopinavir-Ritonavir Combination Induces Endoplasmic Reticulum Stress and Kills Urological Cancer Cells

et al. 2019

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“…For example, suppression of eIF2α dephosphorylation by the salubrinal (ER stress inhibitor; a specific eIF2α phosphorylation-inducing agent) improves the TRAIL-induced apoptosis in human hepatoma HepG2 cells [ 127 ]. The ER stress inducer thapsigargin sensitizes human esophageal cancer EC109 and TE12 cells to TRAIL-induced apoptosis via AMPK activation [ 128 ]. Accordingly, the role of ER stress in TRAIL-induced apoptosis remains controversial and may depend on tissue-specific or TRAIL resistant characters.…”

Section: Interactions Between Trail Wnt Shh Tgfβ and Mirna Sigmentioning

confidence: 99%

TRAIL, Wnt, Sonic Hedgehog, TGFβ, and miRNA Signalings Are Potential Targets for Oral Cancer Therapy

Farooqı

Shu

Huang

et al. 2017

IJMS

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Clinical studies and cancer cell models emphasize the importance of targeting therapies for oral cancer. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is highly expressed in cancer, and is a selective killing ligand for oral cancer. Signaling proteins in the wingless-type mouse mammary tumor virus (MMTV) integration site family (Wnt), Sonic hedgehog (SHH), and transforming growth factor β (TGFβ) pathways may regulate cell proliferation, migration, and apoptosis. Accordingly, the genes encoding these signaling proteins are potential targets for oral cancer therapy. In this review, we focus on recent advances in targeting therapies for oral cancer and discuss the gene targets within TRAIL, Wnt, SHH, and TGFβ signaling for oral cancer therapies. Oncogenic microRNAs (miRNAs) and tumor suppressor miRNAs targeting the genes encoding these signaling proteins are summarized, and the interactions between Wnt, SHH, TGFβ, and miRNAs are interpreted. With suitable combination treatments, synergistic effects are expected to improve targeting therapies for oral cancer.

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“…In our study, we explored the actions of ERS in the anti-NSCLC activities of PT. ER is the main storage site of Ca 2+ , and any disruption in its accumulation can promote ER stress 23 , 33 . Our study found PT treatment could immediately disturb the Ca 2+ homeostasis in ER and cytoplasm, and significantly upregulate cytosolic Ca 2+ levels in PC9 cells.…”

Section: Discussionmentioning

confidence: 99%

Pterostilbene exerts anticancer activity on non-small-cell lung cancer via activating endoplasmic reticulum stress

Yang

et al. 2017

Sci Rep

Self Cite

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Pterostilbene (PT), the natural dimethylated analog of resveratrol (RSV), is a potent anticarcinogen for non-small-cell lung cancer (NSCLC), but its anti-NSCLC mechanisms remain unclear. In this study, we show that PT treatment time- and dose-dependently enhanced the endoplasmic reticulum stress (ERS) signaling (i.e., p-PERK, IRE1, ATF4, CHOP), thus decreasing the cell viability and inducing apoptosis in human PC9 and A549 NSCLC cell lines. Moreover, the decreased migratory and adhesive abilities, downregulation of intracellular glutathione (GSH) level, enhanced reactive oxygen species (ROS) generation, Caspase 3 activity and mitochondrial membrane depolarization were observed in NSCLC cells treated with PT. These effects were reversed by CHOP siRNA which inhibited the ERS signaling pathway, but were promoted by thapsigargin (a classical ERS inducer) in vitro. Besides, in vivo studies also verify that PT exerted anticancer activity by mobilizing ERS signaling and apoptosis-related proteins, and these effects were enhanced by thapsigargin. Therefore, ERS activation may represent a new mechanism of anti-NSCLC action by PT, and a novel therapeutic intervention for lung cancer.

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Thapsigargin sensitizes human esophageal cancer to TRAIL-induced apoptosis via AMPK activation

Cited by 44 publications

References 73 publications

Lopinavir-Ritonavir Combination Induces Endoplasmic Reticulum Stress and Kills Urological Cancer Cells

Lopinavir-Ritonavir Combination Induces Endoplasmic Reticulum Stress and Kills Urological Cancer Cells

TRAIL, Wnt, Sonic Hedgehog, TGFβ, and miRNA Signalings Are Potential Targets for Oral Cancer Therapy

Pterostilbene exerts anticancer activity on non-small-cell lung cancer via activating endoplasmic reticulum stress

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