Docosahexaenoic Acid Enhances Oxaliplatin-Induced Autophagic Cell Death via the ER Stress/Sesn2 Pathway in Colorectal Cancer

Jeong, Soyeon; Kim, Dae Yeong; Kang, Seongwon; Yun, Ho-Gyeong; Kim, Jung Lim; Kim, Bo Ram; Park, Seong Hye; Na, Yoo Jin; Jo, Min Jee; Jeong, Yoon-Su; Kim, Bu Gyeom; Lee, Dong Hoon; Oh, Sang Cheul

doi:10.3390/cancers11070982

Cited by 40 publications

(30 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The upregulation of INHBE is also a marker of the ER-stress induction in DHA-treated cells and may act on cell growth inhibition [77]. The triggering of ER-stress-induced apoptosis by DHA agrees with previous studies using colon, colorectal, and glioma cancer cells [54,[78][79][80] and even in non-alcoholic steatohepatitis patients [81]. In addition, the Glutathione-Specific Gamma-Glutamyl-cyclo-transferase encoded by the CHAC1 gene, which is also upregulated, induces a glutathione depletion that is an important factor for apoptosis initiation and execution, and thus, acts as a pro-apoptotic component of the unfolded protein response pathway by mediating the pro-apoptotic effects of the ATF4-DDIT3/CHOP cascade [82].…”

Section: Antiproliferative Effect and Induction Of Apoptosissupporting

confidence: 82%

Transcriptomic Response of Breast Cancer Cells MDA-MB-231 to Docosahexaenoic Acid: Downregulation of Lipid and Cholesterol Metabolism Genes and Upregulation of Genes of the Pro-Apoptotic ER-Stress Pathway

Chénais

Cornec

Dumont

et al. 2020

IJERPH

View full text Add to dashboard Cite

Despite considerable efforts in prevention and therapy, breast cancer remains a major public health concern worldwide. Numerous studies using breast cancer cell lines have shown the antiproliferative and pro-apoptotic effects of docosahexaenoic acid (DHA). Some studies have also demonstrated the inhibitory effect of DHA on the migration and invasion of breast cancer cells, making DHA a potential anti-metastatic agent. Thus, DHA has shown its potential as a chemotherapeutic adjuvant. However, the molecular mechanisms triggering DHA effects remain unclear, and the aim of this study was to provide a transcriptomic basis for further cellular and molecular investigations. Therefore, MDA-MB-231 cells were treated with 100 µM DHA for 12 h or 24 h before RNA-seq analysis. The results show the great impact of DHA-treatment on the transcriptome, especially after 24 h of treatment. The impact of DHA is particularly visible in genes involved in the cholesterol biosynthesis pathway that is strongly downregulated, and the endoplasmic reticulum (ER)-stress response that is, conversely, upregulated. This ER-stress and unfolded protein response could explain the pro-apoptotic effect of DHA. The expression of genes related to migration and invasion (especially SERPINE1, PLAT, and MMP11) is also impacted by DHA. In conclusion, this transcriptomic analysis supports the antiproliferative, pro-apoptotic and anti-invasive effects of DHA, and provides new avenues for understanding its molecular mechanisms.

show abstract

Section: Antiproliferative Effect and Induction Of Apoptosissupporting

confidence: 82%

Transcriptomic Response of Breast Cancer Cells MDA-MB-231 to Docosahexaenoic Acid: Downregulation of Lipid and Cholesterol Metabolism Genes and Upregulation of Genes of the Pro-Apoptotic ER-Stress Pathway

Chénais

Cornec

Dumont

et al. 2020

IJERPH

View full text Add to dashboard Cite

show abstract

“…ER stress is activated by a variety of factors and triggers the unfolded protein response (UPR), which restores homeostasis or activates cell death (34). Previous studies have reported that UPR signaling pathways are closely related to autophagy, apoptosis, inflammatory response and oxidative stress in cancer cells (35)(36)(37). The PERK/ATF4/CHOP pathway plays an important role in modulating anti-and pro-apoptotic proteins, such as B-cell lymphoma-2 (Bcl-2) family members that control mitochondrial apoptosis (38).…”

Section: Discussionmentioning

confidence: 99%

Salinomycin triggers prostate cancer cell apoptosis by inducing oxidative and endoplasmic reticulum stress via suppressing Nrf2 signaling

Yang

et al. 2021

Exp Ther Med

View full text Add to dashboard Cite

Salinomycin is a polyether antiprotozoal antibiotic that is widely used as an animal food additive. Some antifungal, antiparasitic, antiviral and anti-inflammatory activities have been reported for salinomycin. Recently, the anti-cancer effect of salinomycin has been demonstrated in breast cancer; however, the underlying mechanism remains unknown. The present study aimed to investigate the functional roles of salinomycin in the progression of prostate cancer cells using the DU145 and PC-3 cell lines. Western blotting and reverse transcription-quantitative polymerase chain reaction were performed to detect the expression of oxidative stress and endoplasmic reticulum stress-related molecules, and flow cytometry was performed to detect the apoptosis rate of DU145 and PC-3 cells after salinomycin treatment. The results demonstrated that salinomycin inhibited the viability and induced the apoptosis of PC-3 and DU145 cells in a dose-dependent manner. Furthermore, salinomycin increased the production of reactive oxygen species (ROS) and 8-hydroxy-2'-deoxyguanosine (8-OH-dG) and the lipid peroxidation. In addition, salinomycin induced the activation of unfolded protein response and endoplasmic reticulum stress in DU145 and PC-3 cells, as indicated by the elevated expression of binding immunoglobulin protein, activating transcription factor 4, phosphorylated eukaryotic initiation factor 2α, phosphorylated protein kinase RNA-like endoplasmic reticulum kinase and C/EBP homologous protein.In addition, salinomycin significantly downregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1, NAD(P)H quinone dehydrogenase 1 and glutamate-cysteine ligase catalytic subunit and decreased the activity of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase in PC-3 and DU145 cells. Furthermore, the Nrf2 activator, tert-butylhydroquinone, significantly reversed the therapeutic effects of salinomycin by stimulating the Nrf2 pathway and increasing the activity of antioxidant enzymes. Taken together, these findings demonstrated that salinomycin may trigger apoptosis by inducing oxidative and ER stress in prostate cancer cells via suppressing Nrf2 signaling.

show abstract

“…Autophagic cell death is one of the major mechanisms that induced programmed cell death. It was found that autophagic cell death played an important role in anticancer drugs [20,21]. DHA could induce autophagy in some human cancer cell lines, including esophageal cancer cells [22][23][24], while the precise mechanisms of DHA on cancer cells were still limited.…”

mentioning

confidence: 99%

Autophagy-dependent cell cycle arrest in esophageal cancer cells exposed to dihydroartemisinin

Liao

Liu

et al. 2020

Chin Med

View full text Add to dashboard Cite

Background: Dihydroartemisinin (DHA), a derivate of artemisinin, is an effective antimalarial agent. DHA has been shown to exert anticancer activities to numerous cancer cells in the past few years, while the exact molecular mechanisms remain to be elucidated, especially in esophageal cancer. Methods: Crystal violet assay was conducted to determine the cell viability of human esophageal cancer cell line Eca109 treated with DHA. Tumor-bearing nude mice were employed to evaluate the anticancer effect of DHA in vivo. Soft agar and crystal violet assays were used to measure the tumorigenicity of Eca109 cells. Flow cytometry was performed to evaluate ROS or cell cycle distribution. GFP-LC3 plasmids were delivered into Eca109 cells to visualize autophagy induced by DHA under a fluorescence microscope. The mRNA and protein levels of each gene were tested by qRT-PCR and western blot, respectively. Results: Our results proved that DHA significantly reduced the viability of Eca109 cells in a dose-and time-dependent manner. Further investigation showed that DHA evidently induced cell cycle arrest at the G2/M phase in Eca109 cells. Mechanistically, DHA induced intracellular ROS generation and autophagy in Eca109 cells, while blocking ROS by an antioxidant NAC obviously inhibited autophagy. Furthermore, we found that telomere shelterin component TRF2 was down-regulated in Eca109 cells exposed to DHA through autophagy-dependent degradation, which could be rescued after autophagy was blocked by ROS inhibition. Moreover, the DNA damage response (DDR) was induced obviously in DHA treated cells. To further explore whether ROS or autophagy played a vital role in DHA induced cell cycle arrest, the cell cycle distribution of Eca109 cells was evaluated after ROS or autophagy blocking, and the results showed that autophagy, but not ROS, was essential for cell cycle arrest in DHA treated cells. Conclusion: Taken together, DHA showed anticancer effect on esophageal cancer cells through autophagy-dependent cell cycle arrest at the G2/M phase, which unveiled a novel mechanism of DHA as a chemotherapeutic agent, and the degradation of TRF2 followed by DDR might be responsible for this cell phenotype.

show abstract

Docosahexaenoic Acid Enhances Oxaliplatin-Induced Autophagic Cell Death via the ER Stress/Sesn2 Pathway in Colorectal Cancer

Cited by 40 publications

References 41 publications

Transcriptomic Response of Breast Cancer Cells MDA-MB-231 to Docosahexaenoic Acid: Downregulation of Lipid and Cholesterol Metabolism Genes and Upregulation of Genes of the Pro-Apoptotic ER-Stress Pathway

Transcriptomic Response of Breast Cancer Cells MDA-MB-231 to Docosahexaenoic Acid: Downregulation of Lipid and Cholesterol Metabolism Genes and Upregulation of Genes of the Pro-Apoptotic ER-Stress Pathway

Salinomycin triggers prostate cancer cell apoptosis by inducing oxidative and endoplasmic reticulum stress via suppressing Nrf2 signaling

Autophagy-dependent cell cycle arrest in esophageal cancer cells exposed to dihydroartemisinin

Contact Info

Product

Resources

About