bims-istrec 2021-10-10 papers

Issue of 2021‒10‒10
five papers selected by
Vincenzo Ciminale’s Lab
Istituto Oncologico Veneto

Biomol Ther (Seoul). 2021 Oct 05.

The Endoplasmic Reticulum Stress Response Mediates Shikonin-Induced Apoptosis of 5-Fluorouracil-Resistant Colorectal Cancer Cells.

Mei Jing Piao, Xia Han, Kyoung Ah Kang, Pincha Devage Sameera Madushan Fernando, Herath Mudiyanselage Udari Lakmini Herath, Jin Won Hyun.

Resistance to chemotherapeutic drugs is a significant problem in the treatment of colorectal cancer, resulting in low response rates and decreased survival. Recent studies have shown that shikonin, a naphthoquinone derivative, promotes apoptosis in colon cancer cells and cisplatin-resistant ovarian cells, raising the possibility that this compound may be effective in drug-resistant colorectal cancer. The aim of this study was to characterize the molecular mechanisms underpinning shikonin-induced apoptosis, with a focus on endoplasmic reticulum (ER) stress, in a 5-fluorouracil-resistant colorectal cancer cell line, SNU-C5/5-FUR. Our results showed that shikonin significantly increased the proportion of sub-G1 cells and DNA fragmentation and that shikonin-induced apoptosis is mediated by mitochondrial Ca2+ accumulation. Shikonin treatment also increased the expression of ER-related proteins, such as glucose regulatory protein 78 (GRP78), phospho-protein kinase RNA-like ER kinase (PERK), phospho-eukaryotic initiation factor 2 (eIF2α), phospho-phosphoinositol-requiring protein-1 (IRE1), spliced X-box-binding protein-1 (XBP-1), cleaved caspase-12, and C/EBP-homologous protein (CHOP). In addition, siRNA-mediated knockdown of CHOP attenuated shikonininduced apoptosis, as did the ER stress inhibitor TUDCA. These data suggest that ER stress is a key factor mediating the cytotoxic effect of shikonin in SNU-C5/5-FUR cells. Our findings provide an evidence for a mechanism in which ER stress leads to apoptosis in shikonin-treated SNU-C5/5-FUR cells. Our study provides evidence to support further investigations on shikonin as a therapeutic option for 5-fluorouracil-resistant colorectal cancer.

Keywords: 5-Fluorouracil–resistant colorectal cancer; Apoptosis; Endoplasmic reticulum stress; Naphthoquinone

DOI: https://doi.org/10.4062/biomolther.2021.118

Mol Cancer Ther. 2021 Oct 08. pii: molcanther.MCT-21-0396-A.2021. [Epub ahead of print]

A Benzenesulfonamide-based Mitochondrial Uncoupler Induces Endoplasmic Reticulum Stress and Immunogenic Cell Death in Epithelial Ovarian Cancer.

Fangfang Bi, Ziyan Jiang, Wonmin Park, Tobias Mp Hartwich, Zhiping Ge, Kay Yi Chong, Kevin Yang, Madeline J Morrisson, Dongin Kim, Jaeyeon Kim, Wen Zhang, Liliia M Kril, David S Watt, Chunming Liu, Yang Yang-Hartwich.

Epithelial ovarian cancer (EOC) is a leading cause of death from gynecologic malignancies and requires new therapeutic strategies to improve clinical outcomes. EOCs metastasize in the abdominal cavity through dissemination in the peritoneal fluid and ascites, efficiently adapt to the nutrient-deprived microenvironment, and resist current chemotherapeutic agents. Accumulating evidence suggests that mitochondrial oxidative phosphorylation is critical for the adaptation of EOC cells to this otherwise hostile microenvironment. Although chemical mitochondrial uncouplers can impair mitochondrial functions and thereby target multiple, essential pathways for cancer cell proliferation, traditional mitochondria uncouplers often cause toxicity that precludes their clinical application. In this study, we demonstrated that a mitochondrial uncoupler, specifically 2,5-dichloro-N-(4-nitronaphthalen-1-yl)benzenesulfonamide, hereinafter named Y3, was an antineoplastic agent in ovarian cancer models. Y3 treatment activated AMP-activated protein kinase and resulted in the activation of endoplasmic reticulum stress sensors as well as growth inhibition and apoptosis in ovarian cancer cells in vitro. Y3 was well tolerated in vivo and effectively suppressed tumor progression in three mouse models of EOC, and Y3 also induced immunogenic cell death of cancer cells that involved the release of damage-associated molecular patterns and the activation of antitumor adaptive immune responses. These findings suggest that mitochondrial uncouplers hold promise in developing new anticancer therapies that delay tumor progression and protect ovarian cancer patients against relapse.

DOI: https://doi.org/10.1158/1535-7163.MCT-21-0396

Adv Sci (Weinh). 2021 Oct 03. e2101936

A Novel Mechanism of Endoplasmic Reticulum Stress- and c-Myc-Degradation-Mediated Therapeutic Benefits of Antineurokinin-1 Receptor Drugs in Colorectal Cancer.

Yue Shi, Xi Wang, Yueming Meng, Junjie Ma, Qiyu Zhang, Gang Shao, Lingfei Wang, Xurui Cheng, Xiangyu Hong, Yong Wang, Zhibin Yan, Yihai Cao, Jian Kang, Caiyun Fu.

The neurokinin-1 receptor (NK-1R) antagonists are approved as treatment for chemotherapy-associated nausea and vomiting in cancer patients. The emerging role of the substance P-NK-1R system in oncogenesis raises the possibility of repurposing well-tolerated NK-1R antagonists for cancer treatment. This study reports that human colorectal cancer (CRC) patients with high NK-1R expression have poor survival, and NK-1R antagonists SR140333 and aprepitant induce apoptotic cell death in CRC cells and inhibit CRC xenograft growth. This cytotoxicity induced by treatment with NK-1R antagonists is mediated by induction of endoplasmic reticulum (ER) stress. ER stress triggers calcium release, resulting in the suppression of prosurvival extracellular signal-regulated kinase (ERK)-c-Myc signaling. Along with ER calcium release, one ER stress pathway mediated by protein kinase RNA-like ER kinase (PERK) is specifically activated, leading to increased expression of proapoptotic C/EBP-homologous protein (CHOP). Moreover, NK-1R antagonists enhance the efficacy of chemotherapy by increasing the sensitivity and overcoming resistance to 5-fluorouracil in CRC cells through the induction of sustained ER stress and the consequent suppression of ERK-c-Myc signaling both in vitro and in vivo. Collectively, the findings provide novel mechanistic insights into the efficacy of NK-1R antagonists either as a single agent or in combination with chemotherapy for cancer treatment.

Keywords: ER stress; MAPK signal pathway; chemotherapy resistance; human colorectal cancer; neurokinin-1 receptor

DOI: https://doi.org/10.1002/advs.202101936

Aging (Albany NY). 2021 Oct 05. 13(undefined):

Low expression of endoplasmic reticulum stress-related gene SERP1 is associated with poor prognosis and immune infiltration in skin cutaneous melanoma.

Yuchao Fan, Xiao Liang, Deshui Yu.

Stress-associated endoplasmic reticulum protein 1 (SERP1) is a gene induced by endoplasmic reticulum (ER) stress and a major contributor to multiple tumor types. Skin cutaneous melanoma (SKCM) is a highly aggressive and fatal cancer with poor treatment outcomes after progression. In this study, we evaluated SERP1's role in tumorigenesis, prognosis, and immune infiltration in SKCM. Patients with SKCM had low SERP1 expression. We identified differentially expressed genes between high- and low-SERP1 expression groups and conducted functional, pathway, and gene enrichment analyses. Protein-protein (PPI) and gene-gene interaction (GGI) networks were constructed via STRING and GeneMANIA, respectively. SERP1 mutation information was obtained through cBioPortal; location in the skin was identified through the Human Protein Atlas. Kaplan-Meier analysis revealed an association between low SERP1 expression and overall survival (OS), disease-specific survival (DSS), progress-free interval (PFI) rates, and worse prognosis in patients with multiple clinicopathological features. Cox regression analysis and nomograms further presented SERP1 level as an independent prognostic factor for patients with SKCM. Furthermore, there were significant correlations between SERP1 expression and immune infiltrates; thus, low SERP1 expression is associated with immune cell infiltration and can be considered a poor prognostic biomarker in patients with SKCM. Stress-associated endoplasmic reticulum protein 1 (SERP1) is a gene induced by endoplasmic reticulum (ER) stress and a major contributor to multiple tumor types. Skin cutaneous melanoma (SKCM) is a highly aggressive and fatal cancer with poor treatment outcomes after progression. In this study, we evaluated SERP1's role in tumorigenesis, prognosis, and immune infiltration in SKCM. Patients with SKCM had low SERP1 expression. We identified differentially expressed genes between high- and low-SERP1 expression groups and conducted functional, pathway, and gene enrichment analyses. Protein-protein (PPI) and gene-gene interaction (GGI) networks were constructed via STRING and GeneMANIA, respectively. SERP1 mutation information was obtained through cBioPortal; location in the skin were identified through the Human Protein Atlas. Kaplan-Meier analysis revealed an association between low SERP1 expression and overall survival (OS), disease-specific survival (DSS), progress-free interval (PFI) rates, and worse prognosis in patients with multiple clinicopathological features. Cox regression analysis and nomograms further presented SERP1 level as an independent prognostic factor for patients with SKCM. Furthermore, there were significant correlations between SERP1 expression and immune infiltrates; thus, low SERP1 expression is associated with immune cell infiltration and can be considered a poor prognostic biomarker in patients with SKCM.

Keywords: endoplasmic reticulum stress; immune infiltration; prognosis; skin cutaneous melanoma; stress-associated endoplasmic reticulum protein 1

DOI: https://doi.org/10.18632/aging.203594

Cell Cycle. 2021 Oct 04. 1-11

Cdc25C/cdc2/cyclin B, raf/MEK/ERK and PERK/eIF2α/CHOP pathways are involved in forskolin-induced growth inhibition of MM.1S cells by G2/M arrest and mitochondrion-dependent apoptosis.

Ping Yang, Pei-Wen Jiang, Chen Li, Ming-Xiang Gao, Yi-Song Sun, Dan-Ying Zhang, Wen-Qian Du, Jing Zhao, Song-Ting Shi, Yan Li, Tai Yang, Li Cheng, Min-Hui Li.

Multiple myeloma (MM) remains an incurable hematological malignancy characterized by proliferation and accumulation of plasma cells in the bone marrow. Innovative and effective therapeutic approaches that are able to improve the outcome and the survival of MM sufferers, especially the identification of novel natural compounds and investigation of their anti-MM mechanisms, are needed. Here, we investigated the effects and the potential mechanisms against MM of forskolin, a diterpene derived from the medicinal plant Coleus forskohlii, in MM cell line MM.1S. CCK-8 assay showed that forskolin significantly inhibited MM.1S cells viability in a time- and dose-dependent manner. Furthermore, we demonstrated that forskolin induced G2/M phase arrest with a remarkable increase of p-cdc25c, p-cdc2, and a decrease of cyclin B1, indicating the suppression of cdc25C/cdc2/cyclin B pathway. Moreover, we found that forskolin induced mitochondrion-dependent apoptosis which was accompanied by the increase of pro-apoptotic proteins Bax, Bad, Bim and Bid, the decrease of anti-apoptotic proteins Bcl-2 and Bcl-xl, the changes of the mitochondrial membrane potential (MMP) and increase of cleaved caspase-9, cleaved caspase-3 and cleaved PARP. Of note, we demonstrated that forskolin induced a decrease of p-C-Raf, p-MEK, p-ERK1/2 and p-p90Rsk, and an increase of p-PERK, p-eIF2α and CHOP, which indicated that the inhibition of Raf/MEK/ERK pathway and activation of PERK/eIF2α/CHOP pathway were involved, at least partially, in forskolin-induced MM.1S cells apoptosis. These findings confirm the anti-MM action of forskolin and extend the understanding of its anti-MM mechanism in MM.1S cells, as well as reinforcing the evidence for forskolin as a natural chemotherapeutic compound against MM.

Keywords: G2/M arrest; Multiple myeloma; apoptosis; forskolin; natural compounds

DOI: https://doi.org/10.1080/15384101.2021.1983280