bims-istrec 2022-10-02 papers

Issue of 2022‒10‒02
five papers selected by
the Vincenzo Ciminale lab
Istituto Oncologico Veneto

Andrologia. 2022 Sep 27. e14599

Trabectedin (ET-743) in prostate cancer: Endoplasmic reticulum stress-induced apoptotic effect.

Harika Atmaca, Ferdi Oğuz, Suleyman Ilhan.

Trabectedin is a chemotherapy agent originating from a tunicate, Ecteinascidia turbinata. In this study, DNA-independent action mechanisms of trabectedin are investigated in prostate cancer (PCa) cells. Cell viability was assessed via XTT assay. Apoptosis was evaluated via flow cytometry. Tetramethylrodamine ethyl ester (TMRE) dye was utilized to determine mitochondrial membrane potential (MMP). Cell cycle distribution was investigated via flow cytometric analysis. Reactive oxygen species (ROS) were monitored using fluorescence CM-H2DCFDA dye. Changes in CHOP, p-eIF2α, GRP78 and p-PERK which are endoplasmic reticulum (ER) stress-involved proteins were investigated via western blot. Trabectedin induced cytotoxicity and cell cycle arrest at the G2/M phase. Trabectedin decreased MMP via ROS generation in PCa cells. ER stress-related proteins CHOP, p-eIF2α, GRP78 and p-PERK were also elevated by trabectedin treatment indicating the induction of ER stress-induced apoptosis. The results of this study show that trabectedin may be an effective chemotherapeutic for PCa.

Keywords: ER stress; apoptosis; cytotoxicity; oxidative stress; prostate cancer; trabectedin

DOI: https://doi.org/10.1111/and.14599

Biochem Genet. 2022 Sep 30.

ERp44 Regulates the Proliferation, Migration, Invasion, and Apoptosis of Gastric Cancer Cells Via Activation of ER Stress.

Yongjing Tian, Haibin Sun, Yinshengboer Bao, Haiping Feng, Jian Pang, Riletu En, Hongliang Jiang, Tengqi Wang.

Gastric cancer (GC) is one of the most prevalent malignancies worldwide. Endoplasmic reticulum (ER) stress plays a key role in the progression of GC. Rapid proliferation of tumor cells interferes with ER homeostasis, leading to ER stress and triggering unfolded protein response. Therefore, it is very necessary to investigate abnormally expressed ER resident proteins (ERp) in cancer cells. This study aimed to investigate the possible roles of ERp44. The mRNA and protein expression of genes were detected using qRT-PCR and western blot. Cell apoptosis was calculated using flow cytometry. Cell proliferation was determined using CCK-8 and colony formation assay. Cell migration was detected by wound healing, and cell invasion was measured by transwell assay. We found that ERp44 was obviously decreased in GC tissues. Furthermore, ERp44 overexpression distinctly suppressed the proliferation, migration, and invasion of MGC-803 and KATO III cells. In contrast, apoptosis was promoted by ERp44 overexpression. Furthermore, mechanistic studies revealed that overexpression of ERp44 inhibited malignant biological processes by regulating the eIF-2α/CHOP signaling pathway. Taken together, our data demonstrated that ERp44 regulated the proliferation, migration, invasion, and apoptosis via ERp44/eIF-2α/CHOP axis in GC. Targeting the ERp44and ER stress may be a promising strategy for GC.

Keywords: ERp44; Endoplasmic reticulum; GC cells; Stomach neoplasms

DOI: https://doi.org/10.1007/s10528-022-10281-w

Heliyon. 2022 Sep;8(9): e10607

Glabridin induces paraptosis-like cell death via ER stress in breast cancer cells.

Xiang Cui, Min Cui.

Glabridin, a polyphenolic flavonoid isolated from the root of the glycyrrhiza glabra, has been demonstrated to have anti-tumor properties in human malignancies. This study found that glabridin decreased the viability of human breast cancer MDA-MB-231 and MCF7 cells in a dose-dependent manner that was not involved in the caspase-3 cascade. Glabridin promoted the formation of extensive cytoplasmic vacuolation by increasing the expression of endoplasmic reticulum (ER) stress markers BiP, XBP1s, and CHOP. The transmission electron microscopy and fluorescence with the ER chaperon KDEL suggested that the vacuoles were derived from ER. Glabridin-induced vacuolation was blocked when protein synthesis was inhibited by cycloheximide, demonstrating that protein synthesis is crucial for this process. Furthermore, we determined that glabridin causes loss of mitochondrial membrane potential as well as the production of reactive oxygen species, both of which lead to mitochondrial dysfunction. These features are consistent with a kind of programmed cell death described as paraptosis. This work reports for the first time that glabridin could induce paraptosis-like cell death, which may give new therapeutic approaches for apoptosis-resistant breast cancers.

Keywords: Breast cancer; ER stress; Glabridin; Paraptosis; Vacuolation

DOI: https://doi.org/10.1016/j.heliyon.2022.e10607

Nat Rev Urol. 2022 Sep 27.

The endoplasmic reticulum stress response in prostate cancer.

Claire M de la Calle, Kevin Shee, Heiko Yang, Peter E Lonergan, Hao G Nguyen.

In order to proliferate in unfavourable conditions, cancer cells can take advantage of the naturally occurring endoplasmic reticulum-associated unfolded protein response (UPR) via three highly conserved signalling arms: IRE1α, PERK and ATF6. All three arms of the UPR have key roles in every step of tumour progression: from cancer initiation to tumour growth, invasion, metastasis and resistance to therapy. At present, no cure for metastatic prostate cancer exists, as targeting the androgen receptor eventually results in treatment resistance. New research has uncovered an important role for the UPR in prostate cancer tumorigenesis and crosstalk between the UPR and androgen receptor signalling pathways. With an improved understanding of the mechanisms by which cancer cells exploit the endoplasmic reticulum stress response, targetable points of vulnerability can be uncovered.

DOI: https://doi.org/10.1038/s41585-022-00649-3

Exp Cell Res. 2022 Sep 21. pii: S0014-4827(22)00355-X. [Epub ahead of print] 113362

Histone deacetylase inhibitor panobinostat in combination with rapamycin confers enhanced efficacy against triple-negative breast cancer.

Kunlin Wu, Huihao Zhang, Linlin Zhou, Ling Chen, Caiqin Mo, Sunwang Xu, Junyu Lin, Lingjun Kong, Xiangjin Chen.

Triple-negative breast cancer (TNBC) accounts for about 15% of diagnosed breast cancer patients, which has a poor survival outcome owing to a lack of effective therapies. This study aimed to explore the in vitro and in vivo efficiency of histone deacetylase (HDAC) inhibitor panobinostat (PANO) in combination with mTOR inhibitor rapamycin (RAPA) against TNBC. TNBC cells were treated with PANO, RAPA alone or the combination of drugs, then cell growth and apoptosis were evaluated by CCK-8, colony formation and flow cytometry. Cell migration and invasion were detected by wound healing assay and transwell assay, respectively. ROS production was detected by DCFH-DA staining. Western blotting was performed to detect protein levels. In vivo tumor growth was assessed in nude mice. The expression of cleaved caspase-3 and Ki-67 in tumor tissues was detected by immunofluorescence staining. H&E staining was conducted to observe the pathological changes in heart, liver, and kidney tissues. The combination of PANO and RAPA exerted a stronger role in repressing growth, migration, invasion, and inducing apoptosis of TNBC cells compared with monotherapy. Furthermore, this combination presented a more effective anti-cancer efficacy than a single treatment in the xenograft model without apparent toxic side effects. Importantly, mechanistic studies indicated that PANO and RAPA combination led to ROS overproduction, which subsequently activated endoplasmic reticulum stress. Conclusion: PANO in combination with RAPA exhibits enhanced efficacy against TNBC, which may be considered a promising therapeutic candidate.

Keywords: Endoplasmic reticulum stress; Panobinostat; ROS; Rapamycin; Triple-negative breast cancer

DOI: https://doi.org/10.1016/j.yexcr.2022.113362