Resveratrol interrupts the pro-invasive communication between cancer associated fibroblasts and cholangiocarcinoma cells

Thongchot, Suyanee; Ferraresi, Alessandra; Vidoni, Chiara; Loilome, Watcharin; Yongvanit, Puangrat; Namwat, Nisana; Isidoro, Ciro

doi:10.1016/j.canlet.2018.05.031

Cited by 70 publications

(70 citation statements)

References 62 publications

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“…As representative of CCA, for the next experiments we focused principally on KKU‐100 and KKU‐213 (and its subclone KKU‐214) cell lines, which greatly differ in terms of cell proliferation and migration and response to chemotherapeutics . Cytofluorometric analysis of the cells labeled with Propidium Iodide (PI) after treatment with 50 μM DHA, in the absence or presence of the pan‐caspase inhibitor z‐VAD‐fmk, revealed that cell death with apoptotic feature (hypodiploid‐sub G1 peak) occurred massively in the first 24 h of treatment and further increased at 48 h (Figures A and S2A).…”

Section: Resultsmentioning

confidence: 99%

“…To determine the relevant toxic concentration of DHA, we exposed CCA cells to increasing concentrations of DHA and assayed the cell viability at 24, 48, and 72 h. For this experiment, we employed five CCA cell lines differing for their genomic asset (aneuploidity, oncogenes, and oncosuppressor genes mutations) and biological features (cell proliferation, cell migration, chemoresistance, in vivo tumorigenicity), as reported in the literature. 22,23,[28][29][30][31] The human immortalized cholangiocyte MMNK-1 cell line was included as bile duct epithelial benign counterpart of CCA. Data shown in Figure 1A indicated that 50 μM is the minimum DHA concentration eliciting the highest toxic effect in CCA cells.…”

Section: Dihydroartemisinin Induces Cell Death In Cholangiocarcinommentioning

confidence: 99%

“…As representative of CCA, for the next experiments we focused principally on KKU-100 and KKU-213 (and its subclone KKU-214) cell lines, which greatly differ in terms of cell proliferation and migration 31 and response to chemotherapeutics. 32…”

Section: Dihydroartemisinin Induces Caspase-dependent and Caspase-imentioning

confidence: 99%

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Dihydroartemisinin induces apoptosis and autophagy‐dependent cell death in cholangiocarcinoma through a DAPK1‐BECLIN1 pathway

Thongchot

Vidoni

Ferraresi

et al. 2018

Molecular Carcinogenesis

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Cholangiocarcinoma (CCA) is a very aggressive cancer arising from the malignant transformation of cholangiocytes. Intrahepatic CCA is associated with reactive inflammation and intense fibrosis of the hepatobiliary tract. Dihydroartemisinin (DHA), the active compound found in Artemisia annua, has been shown to possess anti-tumor activity in a variety of human cancers, including hepatoma. Here, we tested the ability of DHA to specifically kill CCA cells and have investigated the underlying mechanisms. DHA induced both apoptosis and autophagy-dependent caspase-independent cell death in many CCA cell lines, while being slightly toxic to immortalized cholangiocytes. DHA induced the expression of many apoptosis- and autophagy-related genes in CCA cells. In particular, it greatly induced the expression of DAPK1, and reduced the interaction of BECLIN1 with BCL-2 while promoting its interaction with PI3KC3. Genetic silencing of DAPK1 prevented DHA-induced autophagy. Pharmacologic and genetic inhibition of BECLIN1 function prevented autophagy and cell death induced by DHA in CCA cells. These data unravel a novel pathway of DHA cancer toxicity and open the possibility to introduce DHA in the therapeutic regimen for the treatment of CCA.

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Section: Resultsmentioning

confidence: 99%

Section: Dihydroartemisinin Induces Cell Death In Cholangiocarcinommentioning

confidence: 99%

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Dihydroartemisinin induces apoptosis and autophagy‐dependent cell death in cholangiocarcinoma through a DAPK1‐BECLIN1 pathway

Thongchot

Vidoni

Ferraresi

et al. 2018

Molecular Carcinogenesis

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“…76 CAF-mediated secretion of IL-6 has also been inhibited by resveratrol, inducing a switch in expression from N-cadherin to E-cadherin in migrating mouse cholangiocarcinoma cells to diminish their invasion and induce autophagy. 77 Additional targets for cancer treatment are MMPs, even though they are not solely expressed by CAFs, and many different MMP inhibitors have been developed and tested in phase 1, 2 and 3 clinical trials. Unfortunately, all clinical trials testing small molecule, broad-spectrum MMP inhibitors in a range of cancer types and stages, to date, have failed to improve clinical outcomes and resulted in major musculoskeletal toxicity in many cases.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Cancer-associated fibroblasts—heroes or villains?

et al. 2019

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Cancer-associated fibroblasts (CAFs) were originally presumed to represent a homogeneous population uniformly driving tumorigenesis, united by their morphology and peritumoural location. Our understanding of CAFs has since been shaped by sophisticated in vitro and in vivo experiments, pathological association and, more recently, ablation, and it is now widely appreciated that CAFs form a group of highly heterogeneous cells with no single overarching marker. Studies have demonstrated that the CAF population contains different subtypes based on the expression of marker proteins with the capacity to promote or inhibit cancer, with their biological role as accomplices or adversaries dependent on many factors, including the cancer stage. So, while CAFs have been endlessly shown to promote the growth, survival and spread of tumours via improvements in functionality and an altered secretome, they are also capable of retarding tumorigenesis via largely unknown mechanisms. It is important to reconcile these disparate results so that the functions of, or factors produced by, tumour-promoting subtypes can be specifically targeted to improve cancer patient outcomes. This review will dissect out CAF complexity and CAF-directed cancer treatment strategies in order to provide a case for future, rational therapies.

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“…The increased cellular stress activates autophagy in cancer-associated fibroblasts as a pro-survival mechanism, which promotes tumor growth, while the decreased autophagy in the fibroblasts counteracts tumor progression [351,352]. In a model of cholangiocarcinoma, resveratrol interfered with the release of cytokines by cancer-associated fibroblasts, which activated autophagic flux in cancer cells and halted their migration [353].…”

Section: Discussionmentioning

confidence: 99%

Polyphenol-Mediated Autophagy in Cancer: Evidence of In Vitro and In Vivo Studies

Benvenuto

Albonici

Focaccetti

et al. 2020

IJMS

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One of the hallmarks of cellular transformation is the altered mechanism of cell death. There are three main types of cell death, characterized by different morphological and biochemical features, namely apoptosis (type I), autophagic cell death (type II) and necrosis (type III). Autophagy, or self-eating, is a tightly regulated process involved in stress responses, and it is a lysosomal degradation process. The role of autophagy in cancer is controversial and has been associated with both the induction and the inhibition of tumor growth. Autophagy can exert tumor suppression through the degradation of oncogenic proteins, suppression of inflammation, chronic tissue damage and ultimately by preventing mutations and genetic instability. On the other hand, tumor cells activate autophagy for survival in cellular stress conditions. Thus, autophagy modulation could represent a promising therapeutic strategy for cancer. Several studies have shown that polyphenols, natural compounds found in foods and beverages of plant origin, can efficiently modulate autophagy in several types of cancer. In this review, we summarize the current knowledge on the effects of polyphenols on autophagy, highlighting the conceptual benefits or drawbacks and subtle cell-specific effects of polyphenols for envisioning future therapies employing polyphenols as chemoadjuvants.

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Resveratrol interrupts the pro-invasive communication between cancer associated fibroblasts and cholangiocarcinoma cells

Cited by 70 publications

References 62 publications

Dihydroartemisinin induces apoptosis and autophagy‐dependent cell death in cholangiocarcinoma through a DAPK1‐BECLIN1 pathway

Dihydroartemisinin induces apoptosis and autophagy‐dependent cell death in cholangiocarcinoma through a DAPK1‐BECLIN1 pathway

Cancer-associated fibroblasts—heroes or villains?

Polyphenol-Mediated Autophagy in Cancer: Evidence of In Vitro and In Vivo Studies

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