scholarly journals Cancer-Associated Fibroblast-Derived IL-6 Determines Unfavorable Prognosis in Cholangiocarcinoma by Affecting Autophagy-Associated Chemoresponse

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2134
Author(s):  
Suyanee Thongchot ◽  
Chiara Vidoni ◽  
Alessandra Ferraresi ◽  
Watcharin Loilome ◽  
Narong Khuntikeo ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Therapeutic Strategy ◽  
Genetic Manipulation ◽  
Molecular Data ◽  
Cancer Associated Fibroblasts ◽  
Apoptotic Response ◽  
Autophagy Flux ◽  
Effective Response ◽  
Cancer Associated Fibroblast

Background: Interleukin-6 (IL-6) released by cancer-associated fibroblasts (CAFs) has been shown to associate with the malignant behavior of cholangiocarcinoma (CCA). Here, we aimed to validate with clinical and molecular data the hypothesis that CAF infiltration and release of IL-6 predict poor prognosis in CCA patients following dysregulation of autophagy in cancer cells. Methods: Stromal IL-6 and cancer-cell-associated autophagy proteins LC3 and p62 were assayed by Tissue MicroArray immunohistochemistry and their expression correlated with overall survival (OS) in a cohort of 70 CCA patients. The 5-FU cytotoxicity and autophagy were determined in CCA cells cultured with CAF-conditioned medium. Results: We show that patients bearing a CCA with low production of stromal IL-6 and active autophagy flux in the cancer cells have the best prognosis and this correlates with a more effective response to post-operative chemotherapy. A similar trend was observed in CCA patients from the TCGA database. In vitro genetic manipulation of IL-6 production by primary CAFs isolated from human CCA showed that IL-6 impairs the autophagy-associated apoptotic response to 5-FU in human CCA cells. Stromal IL-6 inhibition of autophagy in cancer cells was confirmed in an animal model of CCA. Conclusion: Our data support a therapeutic strategy that includes autophagy-enhancing drugs along with adjuvants limiting the stromal inflammation (i.e., the secretion of IL-6) to improve the survival of CCA patients.

scholarly journals Cancer Associated Fibroblast-Derived IL-6 Determines Unfavorable Prognosis in Cholangiocarcinoma By Affecting Autophagy-Associated Chemoresponse

2020 ◽  
Author(s):  
Suyanee Thongchot ◽  
Chiara Vidoni ◽  
Alessandra Ferraresi ◽  
Watcharin Loilome Loilome ◽  
Narong Khuntikeo ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Therapeutic Strategy ◽  
Molecular Data ◽  
Cell Counting ◽  
Effective Response ◽  
Mrna Expression Data ◽  
Cancer Associated Fibroblast ◽  
Related Proteins ◽  
Invasiveness Potential

Abstract Background: Interleukin-6 (IL-6) massively released by cancer-associated fibroblast (CAFs) has been shown to associate with the malignant behavior of cholangiocarcinoma (CCA). In vitro studies demonstrated the ability of CAFs-derived IL-6 to inhibit autophagy in CCA cells thus promoting their proliferation and invasiveness potential. Here, we aimed to validate with clinical and molecular data the hypothesis that CAFs infiltration and release of IL-6 predict poor prognosis in CCA patients following dysregulation of autophagy in cancer cells.Methods: Stromal IL-6 and cancer cell-associated autophagy proteins LC3 and p62 were assayed by Tissue MicroArray immunohistochemistry and their expression correlated with overall survival (OS) in a cohort of 70 CCA patients. Additionally, copy number and mRNA expression data of BECN1, MAP1-LC3B, p62/SQSTM1 and IL6 were extracted from a CCA database in TCGA and correlated with OS. 5-FU Cytotoxicity in CCA cells was assessed by cell counting, clonogenic assay, cytofluorometry and western blotting and immunofluorescence of apoptotic-related proteins. Results: We show that patients bearing a CCA with low production of stromal IL-6 and active autophagy flux in the cancer cells have the best prognosis and this correlates with a more effective response to post-operative chemotherapy. Similar trend was observed in CCA patients from TCGA database. In vitro experiments with primary CAFs isolated from human CCA and epigenetic manipulations showed that IL-6 plays a pivotal role in determining the autophagy-associated apoptotic response to chemotherapeutic drug in cultured human CCA cells. Conclusions: Our data support a therapeutic strategy that includes autophagy-enhancing drugs along with adjuvants limiting the stromal inflammation (i.e., the secretion of IL-6) to improve the survival of CCA patients.

scholarly journals Rapamycin Inhibited Pyroptosis and Reduced the Release of IL-1β and IL-18 in the Septic Response

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Luo Zhuo ◽  
Xiaobing Chen ◽  
Yan Sun ◽  
Yanli Wang ◽  
Yuanfeng Shi ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Genetic Manipulation ◽  
Umbilical Vein ◽  
Disease Model ◽  
Positive Control ◽  
Sepsis Model ◽  
Autophagy Induction ◽  
Immune Imbalance ◽  
Umbilical Vein Endothelial Cells

Pyroptosis, an inflammatory form of programmed cell death, is the initiating event of sepsis and results in immune imbalance by releasing IL-1β and IL-18 in the early stages. Studies show that enhancing autophagy via genetic manipulation can inhibit pyroptosis and prolong the survival of a sepsis animal model, indicating a possible therapeutic strategy against sepsis. However, almost no study so far has achieved pyroptosis inhibition via pharmacological autophagy induction in a sepsis disease model. To this end, we established an in vitro sepsis model by stimulating primary human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS), and analyzed the effect of the autophagy agonist rapamycin (RAPA) on pyroptosis. Phorbol 12-myristate 13-acetate- (PMA-) activated human THP-1 cells were used as the positive control. LPS significantly increased the levels of the pyroptotic protein Gasdermin D (GSDMD), cysteinyl aspartate-specific proteinase 1 (caspase-1), secreted LDH, IL-1β, and IL-18. RAPA treatment downregulated the above factors and enhanced autophagy in the LPS-stimulated HUVECs and THP-1 cells. This study shows that RAPA abrogates LPS-mediated increase in IL-1β and IL-18 by inhibiting pyroptosis and enhancing autophagy.

scholarly journals Nanostructured Dihydroartemisinin Plus Epirubicin Liposomes Enhance Treatment Efficacy of Breast Cancer by Inducing Autophagy and Apoptosis

Nanomaterials ◽  
2018 ◽  
Vol 8 (10) ◽  
pp. 804 ◽  
Author(s):  
Ying-Jie Hu ◽  
Jing-Ying Zhang ◽  
Qian Luo ◽  
Jia-Rui Xu ◽  
Yan Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Therapeutic Strategy ◽  
Beclin 1 ◽  
Type I ◽  
Programmed Death ◽  
Cancer Tissues

The heterogeneity of breast cancer and the development of drug resistance are the relapse reasons of disease after chemotherapy. To address this issue, a combined therapeutic strategy was developed by building the nanostructured dihydroartemisinin plus epirubicin liposomes. Investigations were performed on human breast cancer cells in vitro and xenografts in nude mice. The results indicated that dihydroartemisinin could significantly enhance the efficacy of epirubicin in killing different breast cancer cells in vitro and in vivo. We found that the combined use of dihydroartemisinin with epirubicin could efficiently inhibit the activity of Bcl-2, facilitate release of Beclin 1, and further activate Bax. Besides, Bax activated apoptosis which led to the type I programmed death of breast cancer cells while Beclin 1 initiated the excessive autophagy that resulted in the type II programmed death of breast cancer cells. In addition, the nanostructured dihydroartemisinin plus epirubicin liposomes prolonged circulation of drugs, and were beneficial for simultaneously delivering drugs into breast cancer tissues. Hence, the nanostructured dihydroartemisinin plus epirubicin liposomes could provide a new therapeutic strategy for treatment of breast cancer.

scholarly journals Syrosingopine sensitizes cancer cells to killing by metformin

2016 ◽  
Vol 2 (12) ◽  
pp. e1601756 ◽  
Author(s):  
Don Benjamin ◽  
Marco Colombi ◽  
Sravanth K. Hindupur ◽  
Charles Betz ◽  
Heidi A. Lane ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Drug Combination ◽  
Therapeutic Strategy ◽  
Synthetic Lethality ◽  
Glycolytic Enzyme ◽  
Transformed Cells ◽  
Monoamine Transporters ◽  
Vesicular Monoamine Transporters ◽  
The Individual

We report that the anticancer activity of the widely used diabetic drug metformin is strongly potentiated by syrosingopine. Synthetic lethality elicited by combining the two drugs is synergistic and specific to transformed cells. This effect is unrelated to syrosingopine’s known role as an inhibitor of the vesicular monoamine transporters. Syrosingopine binds to the glycolytic enzyme α-enolase in vitro, and the expression of the γ-enolase isoform correlates with nonresponsiveness to the drug combination. Syrosingopine sensitized cancer cells to metformin and its more potent derivative phenformin far below the individual toxic threshold of each compound. Thus, combining syrosingopine and codrugs is a promising therapeutic strategy for clinical application for the treatment of cancer.

scholarly journals Branched chain amino acid aminotransferase 2 Regulates Ferroptotic Cell Death in Cancer Cells

2020 ◽  
Author(s):  
Kang Wang ◽  
Zhengyang Zhang ◽  
Tsai Hsiang-i ◽  
Yanfang Liu ◽  
Ming Wang ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cancer Cells ◽  
Therapeutic Strategy ◽  
Ectopic Expression ◽  
Branched Chain Amino Acid ◽  
Pancreatic Cancer Cells ◽  
Branched Chain

AbstractFerroptosis has been implicated as a tumor-suppressor function for cancer therapy. Recently the sensitivity to ferroptosis was tightly linked to numerous biological processes, including metabolism of amino acid. Here, using a high-throughput CRISPR/Cas9 based genetic screen in HepG2 cells to search for metabolic proteins inhibiting ferroptosis, we identified branched chain amino acid aminotransferase 2 (BCAT2) as a novel suppressor of ferroptosis. Mechanistically, ferroptosis inducers (erastin, sorafenib and sulfasalazine) activated AMPK/SREBP1 signaling pathway through ferritinophagy, which in turn inhibited BCAT2 transcription. We further confirmed that BCAT2 mediating the metabolism of sulfur amino acid, regulated intracellular glutamate level, whose activation by ectopic expression specifically antagonize system Xc– inhibition and protected liver and pancreatic cancer cells from ferroptosis in vitro and in vivo. Finally, our results demonstrate the synergistic effect of sorafenib and sulfasalazine in downregulating BCAT2 expression and dictating ferroptotic death, where BCAT2 can also be used to predict the responsiveness of cancer cells to ferroptosis-inducing therapies. Collectively, these findings identify a novel role of BCAT2 in ferroptosis, suggesting a potential therapeutic strategy for overcoming sorafenib resistance.

scholarly journals Cancer-associated fibroblasts actively compress cancer cells and modulate mechanotransduction

2021 ◽  
Author(s):  
Jorge Barbazan ◽  
Carlos Perez-Gonzalez ◽  
Manuel Gomez-Gonzalez ◽  
Mathieu Dedenon ◽  
Sophie Richon ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Intrinsic Property ◽  
Cancer Associated Fibroblasts ◽  
Force Transmission ◽  
Force Measurements ◽  
Cancer Cell Growth ◽  
Mechanical Signaling ◽  
Actomyosin Contractility

During tumor progression, cancer-associated fibroblasts (CAFs) accumulate in tumors and produce excessive extracellular matrix (ECM), forming a capsule that enwraps cancer cells. This capsule is a barrier that restricts tumor growth leading to the buildup of intratumoral pressure. Combining genetic and physical manipulations in vivo with microfabrication and force measurements in vitro, we found that the CAFs capsule is not a passive barrier but instead actively compresses cancer cells using actomyosin contractility. Cancer cells mechanosense CAF compression, resulting in an altered localization of the transcriptional regulator YAP. Abrogation of CAFs contractility in vivo leads to the dissipation of compressive forces and impairment of capsule formation. By mapping CAF force patterns in 3D, we show that compression is a CAF-intrinsic property independent of cancer cell growth. Supracellular coordination of CAFs is achieved through fibronectin cables that serve as scaffolds allowing force transmission. Our study unveils that the contractile capsule actively compresses cancer cells, modulates their mechanical signaling, and reorganizes tumor morphology.

scholarly journals Inhibiting lysine 353 oxidation of GRP78 by a hypochlorous probe targeting endoplasmic reticulum promotes autophagy in cancer cells

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Junya Ning ◽  
Zhaomin Lin ◽  
Xuan Zhao ◽  
Baoxiang Zhao ◽  
Junying Miao
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cell Fate ◽  
Hypochlorous Acid ◽  
Dependent Manner ◽  
Autophagy Flux ◽  
Post Translational Modifications

Abstract The level of hypochlorous acid (HOCl) in cancer cells is higher than that in non-cancer cells. HOCl is an essential signal for the regulation of cell fate and works mainly through the protein post-translational modifications in cancer cells. However, the mechanism of HOCl regulating autophagy has not been clarified. Here we reported that a HOCl probe named ZBM-H targeted endoplasmic reticulum and induced an intact autophagy flux in lung cancer cells. Furthermore, ZBM-H promoted the binding of GRP78 to AMPK and increased the phosphorylation of AMPK in a dose- and time-dependent manner. GRP78 knockdown inhibited ZBM-H-induced AMPK phosphorylation and ZBM-H-stimulated autophagy. In addition, mass spectrometry combined with point mutation experiments revealed that ZBM-H increased GRP78 activity by inhibiting HOCl-induced lysine 353 oxidation of GRP78. Following ZBM-H treatment in vitro and in vivo, cell growth was significantly inhibited while apoptosis was induced. Nevertheless, exogenous HOCl partially reversed ZBM-H-inhibited cell growth and ZBM-H-induced GRP78 activation. In brief, we found that an endoplasmic reticulum-targeted HOCl probe named ZBM-H, acting through attenuating HOCl-induced GRP78 oxidation, inhibited tumor cell survival by promoting autophagy and apoptosis. Overall, these data demonstrated a novel mechanism of hypochlorous acid regulating autophagy by promoting the oxidation modification of GRP78.

scholarly journals Cancer-Associated Fibroblasts Differentiated by Exosomes Isolated from Cancer Cells Promote Cancer Cell Invasion

2020 ◽  
Vol 21 (21) ◽  
pp. 8153
Author(s):  
Kimin Kim ◽  
Yeh Joo Sohn ◽  
Ruri Lee ◽  
Hye Ju Yoo ◽  
Ji Yoon Kang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Cell Types ◽  
Cancer Drug ◽  
Cancer Microenvironment ◽  
Cancer Associated Fibroblasts ◽  
Cancer Cell Invasion

Cancer-associated fibroblasts (CAFs) in the cancer microenvironment play an essential role in metastasis. Differentiation of endothelial cells into CAFs is induced by cancer cell-derived exosomes secreted from cancer cells that transfer molecular signals to surrounding cells. Differentiated CAFs facilitate migration of cancer cells to different regions through promoting extracellular matrix (ECM) modifications. However, in vitro models in which endothelial cells exposed to cancer cell-derived exosomes secreted from various cancer cell types differentiate into CAFs or a microenvironmentally controlled model for investigating cancer cell invasion by CAFs have not yet been studied. In this study, we propose a three-dimensional in vitro cancer cell invasion model for real-time monitoring of the process of forming a cancer invasion site through CAFs induced by exosomes isolated from three types of cancer cell lines. The invasiveness of cancer cells with CAFs induced by cancer cell-derived exosomes (eCAFs) was significantly higher than that of CAFs induced by cancer cells (cCAFs) through physiological and genetic manner. In addition, different genetic tendencies of the invasion process were observed in the process of invading cancer cells according to CAFs. Our 3D microfluidic platform helps to identify specific interactions among multiple factors within the cancer microenvironment and provides a model for cancer drug development.

scholarly journals Exosomal miRNA-34 from cancer-associated fibroblasts inhibits growth and invasion of gastric cancer cells in vitro and in vivo

Aging ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 8549-8564 ◽  
Author(s):  
Liang Shi ◽  
Zhenyong Wang ◽  
Xiuchao Geng ◽  
Yuhao Zhang ◽  
Ziqing Xue
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Cancer Associated Fibroblasts ◽  
Gastric Cancer Cells ◽  
Exosomal Mirna

scholarly journals Cancer Associated Fibroblasts Promote Renal Cancer Progression Through a TDO/Kyn/AhR Dependent Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Li-bo Chen ◽  
Shun-ping Zhu ◽  
Tian-pei Liu ◽  
Heng Zhao ◽  
Ping-feng Chen ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Renal Cancer ◽  
Cancer Progression ◽  
Cancer Associated Fibroblasts ◽  
Aromatic Hydrocarbon Receptor ◽  
Cancer Migration ◽  
Tumor Tissues ◽  
Enhanced Secretion

Cancer associated fibroblasts (CAFs) play crucial roles in cancer development, however, the specific mechanisms of CAFs associated renal cancer progression remain poorly understood. Our study observed enriched CAFs in high degree malignant tumor tissues from renal cancer patients. These CAFs isolated from tumor tissues are prone to facilitate drugs resistance and promote tumor progression in vitro and in vivo. Mechanistically, CAFs up-regulated tryptophan 2, 3-dioxygenase (TDO) expression, resulting in enhanced secretion of kynurenine (Kyn). Kyn produced from CAFs could up-regulated the expression of aromatic hydrocarbon receptor (AhR), eventually resulting in the AKT and STAT3 signaling pathways activation. Inhibition of AKT signal prevented cancer cells proliferation, while inhibition of the STAT3 signal reverted drugs resistance and cancer migration induced by kynurenine. Application of AhR inhibitor DMF could efficiently suppress distant metastasis of renal cancer cells, and improve anticancer effects of sorafenib (Sor)/sunitinib (Sun), which described a promising therapeutic strategy for clinical renal cancer.

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