bims-istrec 2022-09-11 papers

bims-istrec

Biomed News

on Integrated stress response in cancer

Issue of 2022‒09‒11
seven papers selected by
the Vincenzo Ciminale lab
Istituto Oncologico Veneto

Gambogenic acid induces apoptosis and autophagy through ROS-mediated endoplasmic reticulum stress via JNK pathway in prostate cancer cells.
HCA (2-Hydroxy-Docosahexaenoic Acid) Induces Apoptosis and Endoplasmic Reticulum Stress in Pancreatic Cancer Cells.
Identification of an endoplasmic reticulum stress-associated gene signature to predict the immune status and prognosis of cutaneous melanoma.
ER Stress Response and Induction of Apoptosis in Malignant Pleural Mesothelioma: The Achilles Heel Targeted by the Anticancer Ruthenium Drug BOLD-100.
Assessment of eIF2α phosphorylation during immunogenic cell death.
Induction of the activating transcription factor-4 in the intratumoral CD8+ T cells sustains their viability and anti-tumor activities.
Countering Triple Negative Breast Cancer via Impeding Wnt/β-Catenin Signaling, a Phytotherapeutic Approach.

Phytother Res. 2022 Sep 09.

Gambogenic acid induces apoptosis and autophagy through ROS-mediated endoplasmic reticulum stress via JNK pathway in prostate cancer cells.

Jianjian Wu, Dejuan Wang, Jiuyao Zhou, Juntao Li, Ruoxin Xie, Yiyuan Li, Jiayu Huang, Bihao Liu, Jianguang Qiu.

  Prostate cancer (PCa) is the most common malignant tumor in males, which frequently develops into castration-resistant prostate cancer (CRPC) with limited therapies. Gambogenic acid (GNA), a flavonoids compound isolated from Gamboge, exhibits anti-tumor capacity in various cancers. Our results showed that GNA revealed not only antiproliferative and pro-apoptotic activities but also the induction of autophagy in PCa cells. In addition, autophagy inhibitor chloroquine enhanced the pro-apoptosis effect of GNA. Moreover, the activation of JNK pathway and the induction of apoptosis and autophagy triggered by GNA were attenuated by JNK inhibitor SP600125. We also found that GNA significantly promoted reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress. Meanwhile, suppressing ER stress with 4-phenylbutyric acid (4-PBA) markedly blocked the activation of JNK pathway induced by GNA. Further research indicated that ROS scavenger N-acetyl-L-cysteine (NAC) effectively abrogated ER stress and JNK pathway activation induced by GNA. Furthermore, NAC and 4-PBA significantly reversed GNA-triggered apoptosis and autophagy. Finally, GNA remarkably suppressed prostate tumor growth with low toxicity in vivo. In conclusion, the present study revealed that GNA induced apoptosis and autophagy through ROS-mediated ER stress via JNK signaling pathway in PCa cells. Thus, GNA might be a promising therapeutic drug against PCa.

Keywords:  JNK pathway; apoptosis; autophagy; gambogenic acid; prostate cancer; reactive oxygen species

DOI:  https://doi.org/10.1002/ptr.7614
Int J Mol Sci. 2022 Aug 31. pii: 9902. [Epub ahead of print]23(17):

HCA (2-Hydroxy-Docosahexaenoic Acid) Induces Apoptosis and Endoplasmic Reticulum Stress in Pancreatic Cancer Cells.

Roberto Beteta-Göbel, Marc Miralles, Javier Fernández-Díaz, Raquel Rodríguez-Lorca, Manuel Torres, Paula Fernández-García, Pablo V Escribá, Victoria Lladó.

  Pancreatic cancer has a high mortality rate due to its aggressive nature and high metastatic rate. When coupled to the difficulties in detecting this type of tumor early and the lack of effective treatments, this cancer is currently one of the most important clinical challenges in the field of oncology. Melitherapy is an innovative therapeutic approach that is based on modifying the composition and structure of cell membranes to treat different diseases, including cancers. In this context, 2-hydroxycervonic acid (HCA) is a melitherapeutic agent developed to combat pancreatic cancer cells, provoking the programmed cell death by apoptosis of these cells by inducing ER stress and triggering the production of ROS species. The efficacy of HCA was demonstrated in vivo, alone and in combination with gemcitabine, using a MIA PaCa-2 cell xenograft model of pancreatic cancer in which no apparent toxicity was evident. HCA is metabolized by α-oxidation to C21:5n-3 (heneicosapentaenoic acid), which in turn also showed anti-proliferative effect in these cells. Given the unmet clinical needs associated with pancreatic cancer, the data presented here suggest that the use of HCA merits further study as a potential therapy for this condition.

Keywords:  ER stress; HCA; apoptosis; membrane lipid therapy; pancreatic cancer

DOI:  https://doi.org/10.3390/ijms23179902
Medicine (Baltimore). 2022 Sep 09. 101(36): e30280

Identification of an endoplasmic reticulum stress-associated gene signature to predict the immune status and prognosis of cutaneous melanoma.

Rong Chen, Linjun Niu, Liang Wu, Youwu He, Gang Liu, Kangjie Hong.

Besides protecting normal cells from various internal and external perturbations, endoplasmic reticulum (ER) stress is also directly related to the pathogenesis of cutaneous melanoma (CM). However, due to the lack of specific molecular biomarkers, ER stress has not been considered a novel treatment target for CM. Here, we identified ER stress-related genes involved in the prognosis of CM patients and constructed an effective model for the prognostic prediction of these patients. First, gene expression data of CM and normal skin tissues from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases were retrieved to identify differentially expressed ER stress-related genes in CM. Meanwhile, an independent cohort obtained from the Gene Expression Omnibus (GEO) database was used for validation. The ER stress genes (ZBP1, DIABLO, GNLY, FASLG, AURKA, TNFRSF21, and CD40LG) that were associated with CM prognosis were incorporated into our prognostic model. The functional analyses indicated that the prognostic model was correlated with patient survival, gender, and cancer growth. Multivariate and univariate Cox regressions revealed that the constructed model could serve as an independent prognostic factor for CM patients. The pathway enrichment analysis showed that the risk model was enriched in different immunity and cancer progression-associated pathways. Moreover, the signature model was significantly connected with the immune subtypes, infiltration of immune cells, immune microenvironment, as well as tumor stem cells. The gene function analysis revealed that 7 ER stress genes were differentially expressed in CM patients and were significantly associated with prognosis and several antitumor drugs. Overall, our current model presented predictive value for the prognosis of CM patients and can be further used in the development of novel therapeutic strategies for CM.

DOI: https://doi.org/10.1097/MD.0000000000030280
Cancers (Basel). 2022 Aug 26. pii: 4126. [Epub ahead of print]14(17):

ER Stress Response and Induction of Apoptosis in Malignant Pleural Mesothelioma: The Achilles Heel Targeted by the Anticancer Ruthenium Drug BOLD-100.

Elia Ranzato, Gregorio Bonsignore, Simona Martinotti.

  Malignant mesothelioma is a rare cancer arising from the serosal surfaces of the body, mainly from the pleural layer. This cancer is strongly related to asbestos exposure and shows a very inauspicious prognosis, because there are scarce therapeutic options for this rare disease. Thus, there is an urgent need to develop novel therapeutic approaches to treat this form of cancer. To explore the biology of malignant pleural mesothelioma (MPM), we previously observed that MPM cell lines show high expression of the GRP78 protein, which is a chaperone protein and the master regulator of the unfolded protein response (UPR) that resides in the endoplasmic reticulum (ER). Based on our previous studies showing the importance of GRP78 in MPM, we observed that BOLD-100, a specific modulator of GRP78 and the UPR, shows cytotoxicity against MPM cells. Our studies demonstrated that BOLD-100 increases ROS production and Ca2+ release from the ER, leading to ER stress activation and, ultimately, to cell death. Our in vitro data strongly suggest that BOLD-100 inhibits the growth of MPM cell lines, proposing the application as a single agent, or in combination with other standard-of-care drugs, to treat MPM.

Keywords:  GRP78; ROS; apoptosis; calcium; endoplasmic reticulum; malignant pleural mesothelioma; mitochondria; unfolded protein response (UPR)

DOI:  https://doi.org/10.3390/cancers14174126
Methods Cell Biol. 2022 ;pii: S0091-679X(22)00003-6. [Epub ahead of print]172 83-98

Assessment of eIF2α phosphorylation during immunogenic cell death.

Lucillia Bezu, Juliette Humeau, Marion Leduc, Hui Pan, Guido Kroemer, Oliver Kepp.

  Immunogenic cell death (ICD) is a modality of cellular demise that when it is induced by certain anticancer treatments can ignite an adaptive anticancer immune response. ICD is characterized by the emission of a specific set of danger-associated molecular patterns (DAMPs) including calreticulin exposure at the plasma membrane, ATP liberation, HMGB1 exodus and type-I IFN release. The apical signaling triggering the appearance of these hallmarks involves the phosphorylation on serine 51 of the α-subunit of eukaryotic initiation factor 2 (EIF2), a key protein in the orchestration of endoplasmic reticulum (ER) stress responses. EIF2α can be phosphorylated by a family of four EIF2A kinases: EIF2AK1-4 (best known as heme regulated inhibitor, HRI, protein kinase R, PKR, protein kinase R-like endoplasmic reticulum kinase, PERK, and general control non-derepressible 2, GCN2), that each respond to a specific type of cellular stress. Here, we describe different techniques to investigate the biochemical pathways leading to eIF2α phosphorylation in the context of ICD.

Keywords:  Endoplasmic reticulum stress; Gene editing; Image analysis; Immunogenic cell death; eIF2α

DOI:  https://doi.org/10.1016/bs.mcb.2022.01.003
Cancer Immunol Immunother. 2022 Sep 05.

Induction of the activating transcription factor-4 in the intratumoral CD8+ T cells sustains their viability and anti-tumor activities.

Zhen Lu, Eun-Ah Bae, Ioannis I Verginadis, Hongru Zhang, Christina Cho, Noreen McBrearty, Subin S George, J Alan Diehl, Constantinos Koumenis, Linda M Bradley, Serge Y Fuchs.

  Immune suppressive factors of the tumor microenvironment (TME) undermine viability and exhaust the activities of the intratumoral cytotoxic CD8 + T lymphocytes (CTL) thereby evading anti-tumor immunity and decreasing the benefits of immune therapies. To counteract this suppression and improve the efficacy of therapeutic regimens, it is important to identify and understand the critical regulators within CD8 + T cells that respond to TME stress and tumor-derived factors. Here we investigated the regulation and importance of activating transcription factor-4 (ATF4) in CTL using a novel Atf4ΔCD8 mouse model lacking ATF4 specifically in CD8 + cells. Induction of ATF4 in CD8 + T cells occurred in response to antigenic stimulation and was further increased by exposure to tumor-derived factors and TME conditions. Under these conditions, ATF4 played a critical role in the maintenance of survival and activities of CD8 + T cells. Conversely, selective ablation of ATF4 in CD8 + T cells in mice rendered these Atf4ΔCD8 hosts prone to accelerated growth of implanted tumors. Intratumoral ATF4-deficient CD8 + T cells were under-represented compared to wild-type counterparts and exhibited impaired activation and increased apoptosis. These findings identify ATF4 as an important regulator of viability and activity of CD8 + T cells in the TME and argue for caution in using agents that could undermine these functions of ATF4 for anti-cancer therapies.

Keywords:  ATF4; Anti-tumor immunity; Antigen activation; CD8 + T cells; Cytotoxic T lymphocytes; Tumor microenvironment and stress

DOI:  https://doi.org/10.1007/s00262-022-03286-2
Plants (Basel). 2022 Aug 24. pii: 2191. [Epub ahead of print]11(17):

Countering Triple Negative Breast Cancer via Impeding Wnt/β-Catenin Signaling, a Phytotherapeutic Approach.

Laleh Arzi, Homa Mollaei, Reyhane Hoshyar.

  Triple negative breast cancer (TNBC) is characterized as a heterogeneous disease with severe malignancy and high mortality. Aberrant Wnt/β-catenin signaling is responsible for self-renewal and mammosphere generation, metastasis and resistance to apoptosis and chemotherapy in TNBC. Nonetheless, in the absence of a targeted therapy, chemotherapy is regarded as the exclusive treatment strategy for the treatment of TNBC. This review aims to provide an unprecedented overview of the plants and herbal derivatives which repress the progression of TNBC through prohibiting the Wnt/β-catenin pathway. Herbal medicine extracts and bioactive compounds (alkaloids, retinoids. flavonoids, terpenes, carotenoids and lignans) alone, in combination with each other and/or with chemotherapy agents could interrupt the various steps of Wnt/β-catenin signaling, i.e., WNT, FZD, LRP, GSK3β, Dsh, APC, β-catenin and TCF/LEF. These phytotherapy agents diminish proliferation, metastasis, breast cancer stem cell self-renewal and induce apoptosis in cell and animal models of TNBC through the down-expression of the downstream target genes of Wnt signaling. Some of the herbal derivatives simultaneously impede Wnt/β-catenin signaling and other overactive pathways in triple negative breast cancer, including: mTORC1; ER stress and SATB1 signaling. The herbal remedies and their bioactive ingredients perform essential roles in the treatment of the very fatal TNBC via repression of Wnt/β-catenin signaling.

Keywords:  Wnt/β-catenin; anti-cancer; bioactive derivative; herbal medicine; triple negative breast cancer

DOI:  https://doi.org/10.3390/plants11172191