FXR agonists enhance the sensitivity of biliary tract cancer cells to cisplatin <i>via</i> SHP dependent inhibition of Bcl-xL expression

Wang, Wei; Zhan, Ming; Li, Qi; Chen, Wei; Chu, Huiling; Huang, Qihong; Hou, Zhaoyuan; Mohan, Man; Wang, Jian

doi:10.18632/oncotarget.8964

Cited by 23 publications

(20 citation statements)

References 48 publications

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“…Our data suggested that activation of FXR by GW4064 acts synergistically with oxaliplatin to exert antitumor e cacy in vitro and in vivo. A previous study proved that FXR is hardly expressed and exhibits loss of function in CRC (41). Advanced stage patients, who are usually recommended to undergo chemotherapy, have better survival after using FXR agonists (9).…”

Section: Discussionmentioning

confidence: 99%

“…Among FXR target genes, SHP is thought to be pivotal in inhibiting tumor growth because it is a cell death receptor that targets mitochondria and induces apoptosis (44). FXR/SHP signaling induces dephosphorylation of STAT3 and inhibits expression of its target Bcl-xL (41). In addition, SHP can translocate to mitochondria, bind to Bcl-2, and cause Cyto C release to the cytoplasm (45).…”

Section: Discussionmentioning

confidence: 99%

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GW4064 Enhances the Chemosensitivity of Colorectal Cancer to Oxaliplatin by Inducing Pyroptosis

Guo

Zheng

et al. 2020

Preprint

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Background Repeated and long-term oxaliplatin therapy leads to drug resistance and severe adverse events, which limit its clinical use. These difficulties highlight the importance of identifying potent and specific drug combinations to enhance the antitumor effects of oxaliplatin. The farnesoid X receptor (FXR) deficiency in colorectal cancer (CRC) suggests that restoring FXR function might be a promising strategy for CRC treatment.Methods A series of in vitro and in vivo experiments were conducted to assess the antitumor effect of the combination of oxaliplatin and FXR agonist GW4064 in CRC. The synergistic mechanism involved was explored.Results A drug combination study showed that the GW4064 acted synergistically with oxaliplatin in colon cancer cells. The combination of oxaliplatin plus GW4064 inhibited cell growth and colony formation, induced apoptosis and pyroptosis in vitro, and slowed tumor growth in vivo. Mechanistically, GW4064 enhanced the chemosensitivity of cells to oxaliplatin by inducing BAX/caspase-3/GSDME-mediated pyroptosis. Furthermore, the combination of oxaliplatin and GW4064 synergistically inhibited STAT3 signaling by restoring SHP expression.Conclusions Our study revealed that GW4064 could enhance the antitumor effects of oxaliplatin against CRC, which provides a novel therapeutic strategy based on a combinational approach for CRC treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

GW4064 Enhances the Chemosensitivity of Colorectal Cancer to Oxaliplatin by Inducing Pyroptosis

Guo

Zheng

et al. 2020

Preprint

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“…Mitochondrial apoptosis, which is induced by DNA damage and cellular stress, is inhibited by the anti-apoptotic Bcl-2 protein Bcl-xL. Bcl-xL is thought to decrease the sensitization of cancer cells to CDDP by stabilizing the Δ Ψ m and preventing the release of apoptosis-inducing molecules such as cytochrome c, Smac and AIF [ 28 ]. In addition, TG2, a Bcl-2 homology 3 (BH3) enzyme involved in protein cross-linking and overexpressed in cancer, has anti-apoptotic effects in cancer cells and plays a key role in the response to CDDP [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Calyxin Y sensitizes cisplatin-sensitive and resistant hepatocellular carcinoma cells to cisplatin through apoptotic and autophagic cell death via SCF βTrCP-mediated eEF2K degradation

et al. 2017

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The down-regulation of eukaryotic elongation factor-2 kinase (eEF2K) is associated with an enhancement in the sensitivity of malignant cells to chemotherapeutic agents. In this study, we found that the silencing of eEF2K enhanced cisplatin (CDDP)-induced cytotoxicity in CDDP-sensitive (HepG2) and resistant (HepG2/CDDP) cells. Calyxin Y, a unique chalcone diarylheptanoid adduct, down-regulated eEF2K by promoting Skp1-Cul1-F-box protein (SCF) β-transducin repeat-containing protein (βTrCP)-mediated protein degradation and synergistically enhanced the cytotoxicity of CDDP. Subsequently, we identified a potential mechanism of this cooperative interaction by showing that the combination of calyxin Y and CDDP enhanced apoptotic cell death via mitochondrial dysfunction. In addition, the combination induced autophagy, which contributed to the synergistic cytotoxic effect. Further research revealed that calyxin Y synergistically sensitized HepG2 and HepG2/CDDP cells to CDDP through enhanced apoptotic and autophagic cell death via the SCF βTrCP-eEF2K pathway. Finally, in vivo studies demonstrated that calyxin Y could enhance the response of HepG2/CDDP cells to CDDP in xenograft models with low systemic toxicity. Thus, the combination of calyxin Y and CDDP might represent an attractive therapeutic strategy for the treatment of chemotherapy-sensitive and resistant hepatocellular carcinoma cells.

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“…Activated STAT3 modulates the function of numerous substrates, including cell proliferation and apoptosis (40). There is ample evidence to indicate that the STAT3 pathway is uncontrolled in GBC (28,41). It was found in our study that LKB1 plays a negative role in GBC cells and inhibits GBC cell growth and metastasis by inactivating STAT3 signaling.…”

Section: Discussionmentioning

confidence: 52%

Tumor suppressor LKB1 inhibits the progression of gallbladder carcinoma and predicts the prognosis of patients with this malignancy

Wang

et al. 2018

Int J Oncol

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Gallbladder carcinoma (GBC) represents the most common fatal tumors of the biliary tract. The 3-year or 5-year survival rate for patients with this disease are 30 and 5%, respectively. Liver kinase B1 (LKB1), a primary upstream kinase of adenosine monophosphate-activated protein kinase (AMPK) necessary for maintaining cell metabolism and energy homeostasis, has been found to be an important tumor suppressor gene in recent years, and its inactivation has also found to be closely associated with tumor growth, metastasis and cancer stem cell (CSC) proliferation. Nevertheless, the function of LKB1 in GBC remains unclear. In this study, we found that the expression of LKB1 in GBC tissues was decreased compared with that in non-cancerous tissues. LKB1 overexpression suppressed the proliferation, metastasis and expansion of GBC CSCs. Mechanically, LKB1 suppressed GBC cell progression via the JAK/signal transducer and activator of transcription 3 (STAT3) pathway. The use of the JAK2 inhibitor, AZD‑1480, attenuated the suppressive effects of LKB1 overexpression on the growth, metastasis and self-renewal ability of the GBC cells, which further demonstrated that JAK/STAT3 was involved in the LKB1-induced suppression of GBC cell growth, metastasis and self-renewal ability. More importantly, the decreased expression of LKB1 was a predictor of a poor prognosis of patients with GBC. On the whole, our data indicate that LKB1 inhibits GBC cell growth, metastasis and self-renewal ability by disrupting JAK/STAT3 signaling, and may thus prove to be a novel prognostic biomarker for patients with GBC.

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FXR agonists enhance the sensitivity of biliary tract cancer cells to cisplatin via SHP dependent inhibition of Bcl-xL expression

Cited by 23 publications

References 48 publications

GW4064 Enhances the Chemosensitivity of Colorectal Cancer to Oxaliplatin by Inducing Pyroptosis

GW4064 Enhances the Chemosensitivity of Colorectal Cancer to Oxaliplatin by Inducing Pyroptosis

Calyxin Y sensitizes cisplatin-sensitive and resistant hepatocellular carcinoma cells to cisplatin through apoptotic and autophagic cell death via SCF βTrCP-mediated eEF2K degradation

Tumor suppressor LKB1 inhibits the progression of gallbladder carcinoma and predicts the prognosis of patients with this malignancy

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