Ginsenoside compound K sensitizes human colon cancer cells to TRAIL-induced apoptosis via autophagy-dependent and -independent DR5 upregulation

Chen, Lei; Yue, Meng; Sun, Qi; Zhang, Zhongyu; Guo, Xiaoqing; Sheng, Xiaotong; Tai, Guihua; Cheng, Hairong; Zhou, Yifa

doi:10.1038/cddis.2016.234

Cited by 89 publications

(82 citation statements)

References 46 publications

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“…Autophagy can inhibit, delay or promote apoptosis (33)(34)(35). The mechansims of autophagy promoting apoptosis may include upregulation of cells susceptible to drug-induced apoptosis and activating of caspases (36,37). In this study, our data showed that apoptosis level was significantly increased with upregulation of autophagy level.…”

Section: Discussionsupporting

confidence: 49%

AKT/mTOR signaling pathway is involved in salvianolic acid B-induced autophagy and apoptosis in hepatocellular carcinoma cells

Gong

Chen

Xia

et al. 2016

International Journal of Oncology

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Chinese medicines are emerging as an attractive new generation of anticancer drugs. Here, we explored the impact of salvianolic acid B (Sal B), the major water-soluble compounds of Danshen, on apoptosis and autophagy of human hepatocellular carcinoma cells (HCC). We also investigated the related molecular mechanisms. We found that Sal B exhibits potent ability to inhibit HCC cells viability in a concentration-dependent manner, and to induce apoptosis via the mitochondrial apoptosis pathway. Additionally, Sal B could also induce autophagy. Furthermore, pretreatment with the autophagy inhibitor chloroquine or 3-methyladenine showed the potential in attenuating the apoptosis rate induced by Sal B. Mechanistically, Sal B treatment inhibited the AKT/mTOR signaling cascade in vitro. Overexpression of AKT abolished the effects of Sal B on HCC cells, suggesting a critical role of the AKT/mTOR signaling pathway in Sal B-induced biological effects. Our results indicated that the mitochondrial pathway was involved in Sal B-induced apoptosis of HCC cells. Moreover, the AKT/mTOR signaling pathway was involved in Sal B-induced autophagy, which promoted apoptosis. This study may provide a promising strategy for using Sal B as a chemotherapeutic agent for patients with HCC.

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Section: Discussionsupporting

confidence: 49%

AKT/mTOR signaling pathway is involved in salvianolic acid B-induced autophagy and apoptosis in hepatocellular carcinoma cells

Gong

Chen

Xia

et al. 2016

International Journal of Oncology

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“…The autophagic degradation of active caspase-8 (34) or TNFRSF10A and TNFRSF10B (42) has been reported as possible mechanisms involved in TRAIL resistance. However, the activation of autophagy flux has been reported to enhance TRAIL-induced extrinsic apoptosis through downregulation of CFLAR (46), and upregulation of TNFRSF10B (47), which are very different from what we have observed in the subpopulation of cell lines and patient samples.…”

Section: Discussioncontrasting

confidence: 99%

17-Hydroxy Wortmannin Restores TRAIL's Response by Ameliorating Increased Beclin 1 Level and Autophagy Function in TRAIL-Resistant Colon Cancer Cells

Dai

Yang

et al. 2019

Molecular Cancer Therapeutics

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Targeting of extrinsic apoptosis pathway by TNF-related apoptosis-inducing ligand (TRAIL) is an attractive approach for cancer therapy. However, two TRAIL drug candidates failed in clinical trials due to lack of efficacy. We identified 17-hydroxy wortmannin (17-HW) in a drug repurposing screen that resensitized TRAIL's response in the resistant colon cancer cells. The deficiency of caspase-8 in drug-resistant cells along with defects in apoptotic cell death was corrected by 17-HW, an inhibitor of PIK3C3-beclin 1 (BECN1) complex and autophagy activity. Further study found that BECN1 significantly increased in the TRAIL-resistant cells, resulting in increased autophagosome formation and enhanced autophagy flux. The extracellular domain (ECD) of BECN1 directly bound to the caspase-8 catalytic subunit (p10), leading to sequestration of caspase-8 in the autophagosome and its subsequent degradation. Inhibition of BECN1 restored the caspase-8 level and TRAIL's apoptotic response in the resistant colon cancer cells. An analysis of 120 colon cancer patient tissues revealed a correlation of a subgroup of patients (30.8%, 37/120) who have high BECN1 level and low caspase-8 level with a poor survival rate. Our study demonstrates that the increased BECN1 accompanied by enhanced autophagy activity is responsible for the TRAIL resistance, and a combination of TRAIL with a PIK3C3-BECN1 inhibitor is a promising therapeutic approach for the treatment of colon cancer. therapy of TRAIL with a BECN1-PIK3C3 complex inhibitor has potential as a new therapeutic approach for the subgroup of patients with colon cancer with an increased BECN1 level plus a reduced full-length caspase-8 level.

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“…As shown in Figure c, CA induced significant autophagosome accumulation, which was characterized by GFP and RFP fluorescence signals (yellow). It has been reported that autophagosome accumulation induces autophagic cell death (Hsin et al, ; Hsin et al, ) and plays a critical role in DR5 upregulation (Chen et al, ). Here, we investigated whether autophagosome accumulation was related to DR5 upregulation by CA.…”

Section: Resultsmentioning

confidence: 99%

Chrysanthemulide A induces apoptosis through DR5 upregulation via JNK‐mediated autophagosome accumulation in human osteosarcoma cells

Zhuo

Zhang

et al. 2018

Journal Cellular Physiology

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Osteosarcoma is the most frequent malignant primary bone tumor, and it generally develops a multidrug resistance. Chrysanthemulide A (CA) is a sesquiterpenoid from the herb Chrysanthemum indicum that has demonstrated a great anti‐osteosarcoma potential. In this study, CA‐induced apoptotic cell death resulted in the activation of the caspase‐8‐mediated caspase cascade, as evidenced by the cleavage of the substrate protein Bid and the caspase‐8 inhibitor Z‐VAD‐FMK. The CA treatment upregulated the expression of death receptor 5 (DR5) in both whole cells and the cell membrane. Blocking DR5 expression by the small interfering RNA (siRNA) treatment decreased the caspase‐8‐mediated caspase cascade and efficiently attenuated CA‐induced apoptosis, suggesting the critical role of DR5 in CA‐induced apoptotic cell death. CA‐induced upregulation of the DR5 protein was accompanied by the accumulation of LC3B‐II, indicating the formation of autophagosomes. Importantly, DR5 upregulation was mediated by transcriptionally controlled autophagosome accumulation, as blockade of autophagosomes by LC3B or ATG‐5 siRNA substantially decreased DR5 upregulation. Furthermore, CA activated the c‐Jun N‐terminal kinase (JNK) signaling pathway, and treatment with JNK siRNAs or inhibitor SP600125 significantly attenuated CA‐mediated autophagosome accumulation and DR5‐mediated cell apoptosis. Finally, CA sensitized the osteosarcoma cells to the DR5 ligand tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐induced apoptotic cell death. Above all, these results suggest that CA induces apoptosis through upregulating DR5 via JNK‐mediated autophagosome accumulation and that combined treatment with CA and TRAIL might be a promising therapy for osteosarcoma.

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Ginsenoside compound K sensitizes human colon cancer cells to TRAIL-induced apoptosis via autophagy-dependent and -independent DR5 upregulation

Cited by 89 publications

References 46 publications

AKT/mTOR signaling pathway is involved in salvianolic acid B-induced autophagy and apoptosis in hepatocellular carcinoma cells

AKT/mTOR signaling pathway is involved in salvianolic acid B-induced autophagy and apoptosis in hepatocellular carcinoma cells

17-Hydroxy Wortmannin Restores TRAIL's Response by Ameliorating Increased Beclin 1 Level and Autophagy Function in TRAIL-Resistant Colon Cancer Cells

Chrysanthemulide A induces apoptosis through DR5 upregulation via JNK‐mediated autophagosome accumulation in human osteosarcoma cells

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