scholarly journals Plumbagin Triggers ER Stress-Mediated Apoptosis in Prostate Cancer Cells via Induction of ROS

2018 ◽  
Vol 45 (1) ◽  
pp. 267-280 ◽  
Author(s):  
Hang Huang ◽  
Hui Xie ◽  
Yue Pan ◽  
Kewen Zheng ◽  
Yiqun Xia ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Er Stress ◽  
Cancer Cells ◽  
Cell Apoptosis ◽  
Folk Medicine ◽  
Endoplasmic Reticulum Stress Response ◽  
Ros Production ◽  
Hormone Refractory ◽  
Stress Activation

Background/Aims: Prostate cancer (PCa) is the second most frequently diagnosed cancer in men worldwide. Currently available therapies for hormone-refractory PCa are only marginally effective. Plumbagin (PLB), a natural naphthoquinone isolated from the traditional folk medicine Plumbago zeylanica, is known to selectively kill tumor cells. Nevertheless, antitumor mechanisms initiated by PLB in cancer cells have not been fully defined. Methods: MTT assay was used to evaluate the effect of PLB on the viability of cancer cells. Cell apoptosis and reactive oxygen species (ROS) production were determined by flow cytometry. Protein expression was detected by western blotting. In vivo anti-tumor effect was measured by using tumor xenoqraft model in nude mice. Results: In the present study, we found that PLB decreases cancer cell growth and induces apoptosis in DU145 and PC-3 cells. In addition, by increasing intracellular ROS levels, PLB induced a lethal endoplasmic reticulum stress response in PCa cells. Importantly, blockage of ROS production significantly reversed PLB-induced ER stress activation and cell apoptosis. In vivo, we found that PLB inhibits the growth of PCa xenografts without exhibiting toxicity Treatment of mice bearing human PCa xenografts with PLB was also associated with induction of ER stress activation. Conclusion: Inducing ER stress by PLB thus discloses a previously unrecognized mechanism underlying the biological activity of PLB and provides an in-depth insight into the action of PLB in the treatment of hormone-refractory PCa.

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 Nonautophagic cytoplasmic vacuolation death induction in human PC-3M prostate cancer by curcumin through reactive oxygen species -mediated endoplasmic reticulum stress

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Wei-Jiunn Lee ◽  
Ming-Hsien Chien ◽  
Jyh-Ming Chow ◽  
Junn-Liang Chang ◽  
Yu-Ching Wen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Treatment Strategies ◽  
Ros Generation ◽  
Ros Production ◽  
Electron Microscopic ◽  
Cytoplasmic Vacuolation

Abstract The antiapoptotic and antiautophagic abilities of cancer cells constitute a major challenge for anticancer drug treatment. Strategies for triggering nonapoptotic or nonautophagic cell death may improve therapeutic efficacy against cancer. Curcumin has been reported to exhibit cancer chemopreventive properties. Herein, we report that curcumin induced apoptosis in LNCaP, DU145 and PC-3 cells but triggered extensive cytoplasmic vacuolation in PC-3M cells. Electron microscopic images showed that the vacuoles lacked intracellular organelles and were derived from the endoplasmic reticulum (ER). Moreover, curcumin-induced vacuolation was not reversed by an apoptosis- or autophagy-related inhibitor, suggesting that vacuolation-mediated cell death differs from classical apoptotic and autophagic cell death. Mechanistic investigations revealed that curcumin treatment upregulated the ER stress markers CHOP and Bip/GRP78 and the autophagic marker LC3-II. In addition, curcumin induced ER stress by triggering ROS generation, which was supported by the finding that treating cells with the antioxidant NAC alleviated curcumin-mediated ER stress and vacuolation-mediated death. An in vivo PC-3M orthotopic prostate cancer model revealed that curcumin reduced tumor growth by inducing ROS production followed by vacuolation-mediated cell death. Overall, our results indicated that curcumin acts as an inducer of ROS production, which leads to nonapoptotic and nonautophagic cell death via increased ER stress.

scholarly journals LncRNA UCA1 promotes development of gastric cancer via the miR-145/MYO6 axis

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
An Yang ◽  
Xin Liu ◽  
Ping Liu ◽  
Yunzhang Feng ◽  
Hongbo Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cell Apoptosis ◽  
Gastric Cancer Cell ◽  
Gastric Cancer Cells ◽  
Gastric Cancer Cell Lines ◽  
Development Of Gastric Cancer

Abstract Background Long noncoding RNA (lncRNA), urothelial carcinoma-associated 1 (UCA1) is aberrantly expressed in multiple cancers and has been verified as an oncogene. However, the underlying mechanism of UCA1 in the development of gastric cancer is not fully understood. In the present study, we aimed to identify how UCA1 promotes gastric cancer development. Methods The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data were used to analyze UCA1 and myosin VI (MYO6) expression in gastric cancer. Western blot and quantitative real-time PCR (QPCR) were performed to test the expression level of the UCA1/miR-145/MYO6 axis in gastric cancer cell lines and tissues. The roles of the UCA1/miR-145/MYO6 axis in gastric cancer in vitro and in vivo were investigated by CCK-8 assay, flow cytometry, siRNAs, immunohistochemistry, and a mouse xenograft model. The targeted relationship among UCA1, miR-145, and MYO6 was predicted using LncBase Predicted v.2 and TargetScan online software, and then verified by luciferase activity assay and RNA immunoprecipitation. Results UCA1 expression was higher but miR-145 expression was lower in gastric cancer cell lines or tissues, compared to the adjacent normal cell line or normal tissues. Function analysis verified that UCA1 promoted cell proliferation and inhibited cell apoptosis in the gastric cancer cells in vitro and in vivo. Mechanistically, UCA1 could bind directly to miR-145, and MYO6 was found to be a downstream target gene of miR-145. miR-145 mimics or MYO6 siRNAs could partly reverse the effect of UCA1 on gastric cancer cells. Conclusions UCA1 accelerated cell proliferation and inhibited cell apoptosis through sponging miR-145 to upregulate MYO6 expression in gastric cancer, indicating that the UCA1/miR-145/MYO6 axis may serve as a potential therapeutic target for gastric cancer.

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