scholarly journals Demethylzeylasteral (T-96) Initiates Extrinsic Apoptosis Against Prostate Cancer cells by Inducing ROS-Mediated ER Stress and Suppressing Autophagic Flux

2021 ◽  
Author(s):  
Dong-Lin Yang ◽  
Ya-jun Zhang ◽  
Liu-jun He ◽  
Chun-sheng Hu ◽  
Li-xia Gao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Er Stress ◽  
Cancer Cells ◽  
Autophagic Flux ◽  
Dependent Manner ◽  
Mechanistic Investigation ◽  
Potential Applications ◽  
Extrinsic Apoptosis ◽  
Pharmacologically Active

Abstract Demethylzeylasteral (T-96), a pharmacologically active triterpenoid monomer extracted from Tripterygiumwilfordii Hook F (TWHF), has been reported to exhibit anti-neoplastic effect on several types of cancer cells. However,whether it has the anti-tumour capability in human Prostate cancer (CaP)cells and what’s the precise regulatory mechanisms underlying the anti-proliferation effect of T-96 on human CaP. In the current study, T-96 exerted significant cytotoxicity to CaP cells in vitro and induced cell cycle arrest at S-phase in a dose-dependent manner. Furthermore, mechanistic investigation indicated that through inducing endoplasmic reticulum (ER) stress caused by intracellular accumulation of reactive oxygen species (ROS), T-96 significantly promoted autophagy initiation while blocked the autophagic flux and finally caused extrinsic apoptosis in CaP cells, implying that ER stress induced byT-96 initiated caspase dependent apoptosis to inhibit CaP cells. Moreover, as a novel lethal ER stress inducer, T-96 was capable to enhance the sensitivity of CaP cells to chemotherapeutic drug cisplatin. Taken together, our data implied that T-96 is a novel ER stress and autophagy modulator, and has the potential applications for CaP therapy in clinic.

scholarly journals Demethylzeylasteral (T-96) initiates extrinsic apoptosis against prostate cancer cells by inducing ROS-mediated ER stress and suppressing autophagic flux

2021 ◽  
Vol 54 (1) ◽  
Author(s):  
Dong-lin Yang ◽  
Ya-jun Zhang ◽  
Liu-jun He ◽  
Chun-sheng Hu ◽  
Li-xia Gao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Er Stress ◽  
Cancer Cells ◽  
Autophagic Flux ◽  
Dependent Manner ◽  
Apoptosis Pathway ◽  
Extrinsic Apoptosis ◽  
Underlying Mechanisms ◽  
Pharmacologically Active

Abstract Background Demethylzeylasteral (T-96) is a pharmacologically active triterpenoid monomer extracted from Tripterygium wilfordii Hook F (TWHF) that has been reported to exhibit anti-neoplastic effects against several types of cancer cells. However, the potential anti-tumour effects of T-96 against human Prostate cancer (CaP) cells and the possible underlying mechanisms have not been well studied. Results In the current study, T-96 exerted significant cytotoxicity to CaP cells in vitro and induced cell cycle arrest at S-phase in a dose-dependent manner. Mechanistically, T-96 promoted the initiation of autophagy but inhibited autophagic flux by inducing ROS-mediated endoplasmic reticulum (ER) stress which subsequently activated the extrinsic apoptosis pathway in CaP cells. These findings implied that T-96-induced ER stress activated the caspase-dependent apoptosis pathway to inhibit proliferation of CaP cells. Moreover, we observed that T-96 enhances the sensitivity of CaP cells to the chemotherapeutic drug, cisplatin. Conclusions Taken together, our data demonstrated that T-96 is a novel modulator of ER stress and autophagy, and has potential therapeutic applications against CaP in the clinic.

scholarly journals Effect of Palmitic Acid on Exosome-Mediated Secretion and Invasive Motility in Prostate Cancer Cells

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2722
Author(s):  
Ivan V. Maly ◽  
Wilma A. Hofmann
Keyword(s):  
Prostate Cancer ◽  
Palmitic Acid ◽  
Cancer Cells ◽  
Dependent Manner ◽  
Prostate Cancer Cells ◽  
Concentration Dependent Manner ◽  
Fat Consumption ◽  
Progression Markers

High fat consumption can enhance metastasis and decrease survival in prostate cancer, but the picture remains incomplete on the epidemiological and cell-biological level, impeding progress toward individualized recommendations in the clinic. Recent work has highlighted the role of exosomes secreted by prostate cancer cells in the progression of the disease, particularly in metastatic invasion, and also the utility of targeting these extracellular vesicles for diagnostics, as carriers of disease progression markers. Here, we investigated the question of a potential impact of the chief nutritional saturated fatty acid on the exosome secretion. Palmitic acid decreased the secretion of exosomes in human prostate cancer cells in vitro in a concentration-dependent manner. At the same time, the content of some prospective metastatic markers in the secreted exosomal fraction was also reduced, as was the ability of the cells to invade across extracellular matrix barriers. While by themselves our in vitro results imply that on the cell level, palmitic acid may be beneficial vis-à-vis the course of the disease, they also suggest that, by virtue of the decreased biomarker secretion, palmitic acid has the potential to cause unjustified deprioritization of treatment in obese and lipidemic men.

scholarly journals Arginine is an epigenetic regulator targeting TEAD4 to modulate OXPHOS in prostate cancer cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chia-Lin Chen ◽  
Sheng-Chieh Hsu ◽  
Tan-Ya Chung ◽  
Cheng-Ying Chu ◽  
Hung-Jung Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Dependent Manner ◽  
Prostate Cancer Cells ◽  
Cancer Cell Growth ◽  
Prostate Carcinogenesis ◽  
Arginine Deprivation ◽  
Epigenetic Regulator

AbstractArginine plays diverse roles in cellular physiology. As a semi-essential amino acid, arginine deprivation has been used to target cancers with arginine synthesis deficiency. Arginine-deprived cancer cells exhibit mitochondrial dysfunction, transcriptional reprogramming and eventual cell death. In this study, we show in prostate cancer cells that arginine acts as an epigenetic regulator to modulate histone acetylation, leading to global upregulation of nuclear-encoded oxidative phosphorylation (OXPHOS) genes. TEAD4 is retained in the nucleus by arginine, enhancing its recruitment to the promoter/enhancer regions of OXPHOS genes and mediating coordinated upregulation in a YAP1-independent but mTOR-dependent manner. Arginine also activates the expression of lysine acetyl-transferases and increases overall levels of acetylated histones and acetyl-CoA, facilitating TEAD4 recruitment. Silencing of TEAD4 suppresses OXPHOS functions and prostate cancer cell growth in vitro and in vivo. Given the strong correlation of TEAD4 expression and prostate carcinogenesis, targeting TEAD4 may be beneficially used to enhance arginine-deprivation therapy and prostate cancer therapy.

Amiloride effects on abiraterone antiproliferative activity in prostate cancer cells in vitro and on clinical management of abiraterone induced mineralocorticoid excess syndrome.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 175-175 ◽  
Author(s):  
Francesca Valcamonico ◽  
Francesca Bedussi ◽  
Diego Galli ◽  
Alberto Dalla Volta ◽  
Martina Fragni ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Clinical Management ◽  
Proliferative Activity ◽  
Complete Disappearance ◽  
Dependent Manner ◽  
Prostate Cancer Cells ◽  
Androgen Synthesis ◽  
Aldosterone Receptor

175 Background: Abiraterone acetate (AA) deeply inhibits androgen synthesis but leads to an ACTH driven increase in mineralocorticoid hormones requiring glucocorticoid supplementation that may impair its antineoplastic efficacy. New strategies for the management of the AA induced mineral corticoid excess syndrome (MCES) are warranted. Methods: We analyzed in vitro the interaction in terms of proliferative activity of AA plus/minus prednisone with the steroid aldosterone receptor antagonists: eplerenone, spironolactone, a non-steroidal aldosterone receptor antagonist (PF-03882845) and the epithelial sodium channel antagonist amiloride. LNCaP were grown in a medium with charcoal-treated serum and concentration-response curves for each studied drug were performed. Besides, the activity of amiloride plus hydrochlorothiazide was assessed in the clinical management of AA induced MCES in 5 consecutive patients with castrate resistant prostate cancer. The recovery of AA induced MCES symptoms and signs was the primary end point. Results: Prednisone, spironolactone and eplerenone induced an increase in the LNCAP proliferation rate and antagonized the AA-induced reduction of the cell proliferation in a concentration-dependent manner, while PF-03882845 did not. Amiloride at high concentrations induced cell death. When combined with AA +/- prednisone, amiloride at low concentration did not interfere with AA anti-proliferative activity however an additive inhibitory effect was observed at higher concentrations. The association of amiloride with hydrochlorothiazide led to a complete disappearance of all clinical and biochemical signs of abiraterone induced MCES in the 5 treated patients. Conclusions: Amiloride and PF-03882845 do not negatively interfere with the AA inhibition of proliferative activity of prostate cancer cells in vitro. The association of amiloride plus hydrochlorothiazide is efficacious in the management AA induced MCES.

scholarly journals ER stress drives Lipocalin 2 upregulation in prostate cancer cells in an NF-κB-dependent manner

BMC Cancer ◽  
2011 ◽  
Vol 11 (1) ◽  
Author(s):  
Navin R Mahadevan ◽  
Jeffrey Rodvold ◽  
Gonzalo Almanza ◽  
Antonio Fernández Pérez ◽  
Matthew C Wheeler ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Er Stress ◽  
Cancer Cells ◽  
Dependent Manner ◽  
Lipocalin 2 ◽  
Prostate Cancer Cells

In vitro and in vivo investigations of novel 1,4-napthoquinone sulphomethylene carbohydrate conjugates in prostate cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 104-104
Author(s):  
Tobias Busenbender ◽  
Sergey Dyshlovoy ◽  
Moritz Kaune ◽  
Lukas Boeckelmann ◽  
Tobias Lange ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Er Stress ◽  
Cancer Cells ◽  
Warburg Effect ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Apoptotic Pathway ◽  
The Warburg Effect

104 Background: The Warburg effect describes the ability of cancer cells to consume larger amounts of glucose in comparison to normal tissue, due to the overexpression of insulin-independent glucose transporters (e.g. GLUT1). This effect can be used to enhance the selectivity and reduce side effects of cytotoxic anticancer molecules by its conjugation to sugar residues, thus, generating cytotoxic agents showing higher selectivity to cancer cells. In continuation of our research on anticancer natural 1,4-naphthoquinones we have investigated a large series of novel semi-synthetic molecules containing 1,4-naphthoquinones element conjugated with glucose molecule via -S-CH2- bond. Methods: We performed screening examinations for 35 novel synthetic molecules in human prostate cancer in vitro. The selected most active compounds were tested in several human prostate cancer cell lines harboring different levels of drug resistance, as well as in non-malignant cells to specify their selectivity. Compounds with the highest cytotoxicity and selectivity were further investigated. The mode of action was assessed including effects on apoptosis induction, oxidative stress, mitochondria, AR-signaling as well as glucose uptake and ER stress were assessed. In vivo dose finding and efficacy analyses were performed. Results: We identified two promising derivatives, showing IC50s at low micro- and nanomolar concentrations. Glucose depletion from the culture media led to increased cytotoxicity and cotreatment with a GLUT1-inhibitor showed an antagonistic effect, suggesting a concurrent uptake and therefore a Warburg effect targeting. The selected compounds exhibited most pronounced cytotoxic activity in DU145 cells as well as 22Rv1 cells. Non-malignant cells were generally less affected. The mode of action involves a loss of mitochondrial membrane potential, a release of cytochrome c and AIF into the cytosol and an upregulation of caspase-9, caspase-3 and cleaved PARP, as well as downregulation of Bcl-2 and Survivin, indicating that mitochondria are a major target, leading to the activation of the intrinsic apoptotic pathway. Early events in treated cells are ROS production and calcium release into the cytosol, a marker of ER-stress. Furthermore, downregulation of the AR and its signaling was observed on mRNA- and protein-level. In vivo experiments revealed antitumor activity in a 22Rv1-xenograft mouse model without severe side effects. Conclusions: In conclusion, we were able to identify two glucose-conjugated 1,4-naphthoquinones exhibiting potent in vitro and in vivoactivity and selectivity in human prostate cancer cells due to the Warburg effect targeting. Cytotoxic activity was exerted via initial ROS production and ER stress leading to mitochondrial damage and the induction of the intrinsic apoptotic pathway.

scholarly journals The Omega-3 Polyunsaturated Fatty Acid DHA Induces Simultaneous Apoptosis and Autophagy via Mitochondrial ROS-Mediated Akt-mTOR Signaling in Prostate Cancer Cells Expressing Mutant p53

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Soyeon Shin ◽  
Kaipeng Jing ◽  
Soyeon Jeong ◽  
Nayeong Kim ◽  
Kyoung-Sub Song ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Mtor Signaling ◽  
Autophagic Flux ◽  
Mutant P53 ◽  
Dependent Manner ◽  
Omega 3 ◽  
Prostate Cancer Cells ◽  
Mitochondrial Ros

Docosahexaenoic acid (DHA) induces autophagy-associated apoptotic cell death in wild-type p53 cancer cells via regulation of p53. The present study investigated the effects of DHA on PC3 and DU145 prostate cancer cell lines harboring mutant p53. Results show that, in addition to apoptosis, DHA increased the expression levels of lipidated form LC3B and potently stimulated the autophagic flux, suggesting that DHA induces both autophagy and apoptosis in cancer cells expressing mutant p53. DHA led to the generation of mitochondrial reactive oxygen species (ROS), as shown by the mitochondrial ROS-specific probe mitoSOX. Similarly, pretreatment with the antioxidant N-acetyl-cysteine (NAC) markedly inhibited both the autophagy and the apoptosis triggered by DHA, indicating that mitochondrial ROS mediate the cytotoxicity of DHA in mutant p53 cells. Further, DHA reduced the levels of phospho-Akt and phospho-mTOR in a concentration-dependent manner, while NAC almost completely blocked that effect. Collectively, these findings present a novel mechanism of ROS-regulated apoptosis and autophagy that involves Akt-mTOR signaling in prostate cancer cells with mutant p53 exposed to DHA.

scholarly journals The Chemokine Receptor CCR3 Is Potentially Involved in the Homing of Prostate Cancer Cells to Bone: Implication of Bone-Marrow Adipocytes

2021 ◽  
Vol 22 (4) ◽  
pp. 1994
Author(s):  
Adrien Guérard ◽  
Victor Laurent ◽  
Gaëlle Fromont ◽  
David Estève ◽  
Julia Gilhodes ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Marrow ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Prostate Gland ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Primary Tumors ◽  
Bone Marrow Adipocytes

Bone metastasis remains the most frequent and the deadliest complication of prostate cancer (PCa). Mechanisms leading to the homing of tumor cells to bone remain poorly characterized. Role of chemokines in providing navigational cues to migrating cancer cells bearing specific receptors is well established. Bone is an adipocyte-rich organ since 50 to 70% of the adult bone marrow (BM) volume comprise bone marrow adipocytes (BM-Ads), which are likely to produce chemokines within the bone microenvironment. Using in vitro migration assays, we demonstrated that soluble factors released by human primary BM-Ads are able to support the directed migration of PCa cells in a CCR3-dependent manner. In addition, we showed that CCL7, a chemokine previously involved in the CCR3-dependent migration of PCa cells outside of the prostate gland, is released by human BM-Ads. These effects are amplified by obesity and ageing, two clinical conditions known to promote aggressive and metastatic PCa. In human tumors, we found an enrichment of CCR3 in bone metastasis vs. primary tumors at mRNA levels using Oncomine microarray database. In addition, immunohistochemistry experiments demonstrated overexpression of CCR3 in bone versus visceral metastases. These results underline the potential importance of BM-Ads in the bone metastatic process and imply a CCR3/CCL7 axis whose pharmacological interest needs to be evaluated.

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