bims-istrec 2022-03-06 papers

Issue of 2022‒03‒06
four papers selected by
Vincenzo Ciminale’s Lab
Istituto Oncologico Veneto

Eur J Pharmacol. 2022 Feb 25. pii: S0014-2999(22)00081-4. [Epub ahead of print]920 174820

miR-340-5p affects oral squamous cell carcinoma (OSCC) cells proliferation and invasion by targeting endoplasmic reticulum stress proteins.

Deming Ou, Ying Wu, Jibin Zhang, Jun Liu, Zeyu Liu, Minfeng Shao, Xiaoying Guo, Shiman Cui.

Lip and oral cancer is the 12th most common malignancy and oral squamous cell carcinoma (OSCC) represents about 90% of all oral malignant tumors, with an annual mortality rate exceeding 50%. Recent studies have concluded that endoplasmic reticulum stress may have a close link to tumor genesis, progression, and prognosis. As an epigenetic regulatory factor, miRNA exerts a substantial effect on tumor development. This study found that transcription factor 6 (ATF6) and Protein kinase R-like endoplasmic reticulum kinase (PERK) were abnormally increased within OSCC tissue samples and oral cancer cell lines. The biological functions of ATF6 and PERK within CAL-27 and SCC-9 oral cancer cell lines were investigated. In vitro experiments revealed that silencing ATF6 and PERK suppressed the ability of cells to proliferate and to invade and mitigated cell endoplasmic reticulum (ER) stress. As predicted by bioinformatics analyses and experiments, miR-340-5p could simultaneously bind to ATF6 and PERK 3' untranslated region (UTR) and inhibit ATF6 and PERK expression. miR-340-3p overexpression inhibited while down-regulation of miR-340-5p boosted the invading and proliferating ability of oral cancer cells, and miR-340-3p also affects ER stress. When co-transfected in oral cancer cells, dynamic effects of miR-340-5p and its targets PERK and ATF6 on cell phenotypes in vitro and in vivo were investigated. PERK or ATF6 overexpression dramatically attenuated phenotypes of miR-340-5p up-regulation. Altogether, miR-340-5p targets the endoplasmic reticulum stress proteins PERK and ATF6 to affect OSCC cell proliferation and invasion.

Keywords: Oral squamous cell carcinoma (OSCC); Protein kinase R-like endoplasmic reticulum kinase (PERK); Transcription factor 6 (ATF6); miR-340-5p

DOI: https://doi.org/10.1016/j.ejphar.2022.174820

Food Funct. 2022 Mar 02.

Resveratrol drives cancer cell senescence via enhancing p38MAPK and DLC1 expressions.

Yan Bian, Xingjie Wang, Zhaodi Zheng, Guanghui Ren, Hongyan Zhu, Mengxue Qiao, Guorong Li.

Pro-senescence therapy is a recently proposed anti-cancer strategy and has been shown to effectively inhibit cancer. Resveratrol is gaining attention for its cancer preventive and suppressive properties. The mechanisms of resveratrol in cancer suppression by inducing cancer cell senescence are unclear. Our results showed that resveratrol induced cell senescence along with an increase of SA-β-Gal activity and inhibition of colony formation in breast and lung cancer cells. The underlying mechanisms were that resveratrol induced ER-stress by increasing SIRT1 to promote p38MAPK expression and by reducing NO level to up-regulate DLC1 expression, and ER-stress further resulted in DNA damage and mitochondrial dysfunction, eventually leading to cancer cell senescence. Our findings on resveratrol's induction of cancer cell senescence via activating ER-stress through the SIRT1/p38MAPK and NO/DLC1 pathways provide a solid base for its clinical application and its preventive application as a food additive.

DOI: https://doi.org/10.1039/d1fo02365a

Acta Biochim Pol. 2022 Mar 02. 69(1): 245-250

Anticancer effects of Pimaric acid is mediated via endoplasmic reticulum stress, caspase-dependent apoptosis, cell cycle arrest, and inhibition of cell migration in human ovarian cancer cells.

Wang Li, Gao Xuemei, Zhu Yilin, Wang Han, Hu Yajun, He Yi, Zhu Zhongxiang.

Pimaric acid is a naturally occurring resin and has been found to perform many pharmacological activities including, anticancer activity. However, the role of Pimaric acid in ovarian cancer is still not known. This investigation aimed to evaluate the anticancer effects of Pimaric acid and its molecular mechanism in human ovarian cancer cells. MTT assay was used to examine cell viability. Cell morphology was determined through phase contrast microscopy. DAPI staining and TUNEL assay were performed for apoptotic study. Examination of cell cycle phase distribution was carried out through flow cytometry. In vitro wound healing assay was used for cell migration determination. Pimaric acid induced cytotoxicity in human ovarian cancer cells (PA-1) in a dose-dependent manner without causing too much cytotoxicity in human ovarian epithelial cells (T1074). Cell morphology in treated cancer cells showed significant changes compared to untreated controls. Furthermore, it was observed that the cytotoxic effects of Pimaric acid were apoptosis-mediated and caspase-dependent cascade. Western blotting analysis showed that the expression of apoptosis-associated proteins like BAX, p-53 and caspase-3 was enhanced and BCL-2 expression was diminished. The induction of cytotoxicity was mediated via endoplasmic reticulum stress through expressions of related proteins which showed a tremendous increase in p-PERK, PERK, AT-4, CHOP and IRE-1 levels after treatment. Cell cycle analysis through cytometry showed significant results as it revealed G2/M phase cell cycle arrest. Furthermore, the in vitro wound healing assay showed specific anti-migratory effects of Pimaric acid on PA-1 cells. In conclusion it can be assumed that Pimaric acid may act as a potential anticancer agent against ovarian carcinoma, however further investigations are required to validate this initial claim.

DOI: https://doi.org/10.18388/abp.2020_6011

Front Genet. 2021 ;12 730847

Roles and Clinical Significances of ATF6, EMC6, and APAF1 in Prognosis of Pancreatic Cancer.

Wang Xiao, Rong-Chang Cao, Wan-Jun Yang, Jie-Hui Tan, Ruo-Qi Liu, He-Ping Kan, Lei Zhou, Na Zhang, Zhi-Ye Chen, Xue-Mei Chen, Jia Xu, Guo-Wei Zhang, Peng Shen.

Background: Pancreatic cancer (PC) is prevalent among malignant tumors with poor prognosis and lacks efficient therapeutic strategies. Endoplasmic reticulum (ER) stress and apoptosis are associated with chronic inflammation and cancer progression. However, the prognostic value of ER stress-related, and apoptosis-related genes in PC remains to be further elucidated. Our study aimed at confirming the prognostic values of the ER stress-related genes, ATF6, EMC6, XBP1, and CHOP, and the apoptosis-related gene, APAF1, in PC patients. Methods: Gene Expression Profiling Interactive Analysis 2 (GEPIA2) was used to evaluate prognosis value of ATF6, EMC6, XBP1, CHOP, and APAF1 in PC. Clinical data from 69 PC patients were retrospectively analyzed. Immunohistochemistry, Western blotting, and qRT-PCR were used for the assessment of gene or protein expression. The cell counting kit-8 (CCK-8) and the Transwell invasion assays were, respectively, used for the assessment of the proliferative and invasive abilities of PC cells. The prognostic values of ATF6, XBP1, CHOP, EMC6, and APAF1 in PC patients were evaluated using Kaplan-Meier and Cox regression analyses. Results: XBP1 and CHOP expressions were not associated with PC recurrence-free survival (RFS), overall survival (OS) and disease-specific survival (DSS). ATF6 upregulation and EMC6 and APAF1 downregulations significantly correlated with the poor RFS, OS, and DSS of PC patients. ATF6 promoted PC cell proliferation and invasion, while EMC6 and APAF1 inhibited these events. Conclusion: ATF6 upregulation and EMC6 and APAF1 downregulations may be valid indicators of poor prognosis of PC patients. Moreover, ATF6, EMC6, and APAF1 may constitute potential therapeutic targets in PC patients.

Keywords: ATF6; Apaf1; EMC6; apoptosis; endoplasmic reticulum stress (ER stress); pancreatic cancer; prognosis

DOI: https://doi.org/10.3389/fgene.2021.730847