bims-istrec 2021-09-12 papers

bims-istrec

Biomed News

on Integrated stress response in cancer

Issue of 2021–09–12
ten papers selected by
the Vincenzo Ciminale lab, Istituto Oncologico Veneto

[Stress granules, emerging players in cancer research].
Schizandrin A induces the apoptosis and suppresses the proliferation, invasion and migration of gastric cancer cells by activating endoplasmic reticulum stress.
Bypassing the Resistance Mechanisms of the Tumor Ecosystem by Targeting the Endoplasmic Reticulum Stress Pathway Using Ruthenium- and Osmium-Based Organometallic Compounds: An Exciting Long-Term Collaboration with Dr. Michel Pfeffer.
Demethylzeylasteral (T-96) initiates extrinsic apoptosis against prostate cancer cells by inducing ROS-mediated ER stress and suppressing autophagic flux.
Docosahexaenoic acid monoglyceride induces apoptosis and autophagy in breast cancer cells via lipid peroxidation-mediated endoplasmic reticulum stress.
Pristimerin induces apoptosis and tumor inhibition of oral squamous cell carcinoma through activating ROS-dependent ER stress/Noxa pathway.
Targeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer.
The Novel Antitumor Compound HCA Promotes Glioma Cell Death by Inducing Endoplasmic Reticulum Stress and Autophagy.
Targeting GRP78 enhances the sensitivity of HOS osteosarcoma cells to pyropheophorbide-α methyl ester-mediated photodynamic therapy via the Wnt/β-catenin signaling pathway.
The Role of ER Stress-Related Phenomena in the Biology of Malignant Peripheral Nerve Sheath Tumors.

Med Sci (Paris). 2021 Aug-Sep;37(8-9):37(8-9): 735-741

[Stress granules, emerging players in cancer research].

Pauline Chavrier, Émilie Mamessier, Anaïs Aulas.

Cancer cells are submitted to numerous stresses during tumor development, such as hypoxia, lack of nutrient, oxidative stress, or mechanical constriction. A complex mechanism termed the integrated stress response (ISR) occurs allowing cell survival. This mechanism leads to the formation of membraneless cytoplasmic structures called stress granules. The hypothesis that these structures play a major role during tumorigenesis has recently emerged. Here, we describe the biological function of stress granules and of proteins that their formation. We also present the current evidences for their involvement in the development of tumors and in the tumor resistance to cancer drugs. Finally, we discuss the interest of targeting stress granule formation to enhance treatment efficiency in order to delay tumor progression.

DOI: https://doi.org/10.1051/medsci/2021109
Mol Med Rep. 2021 Nov;pii: 787. [Epub ahead of print]24(5):

Schizandrin A induces the apoptosis and suppresses the proliferation, invasion and migration of gastric cancer cells by activating endoplasmic reticulum stress.

Huachao Pu, Qian Qian, Fuli Wang, Minjie Gong, Xinguo Ge.

  Apart from its basic antioxidant and anti‑inflammatory properties, schizandrin A (SchA), which is isolated from Fructus schisandra, can exert anticancer effects on multiple cancer types. However, to the best of our knowledge, there has been no study identifying the impacts of SchA on gastric cancer (GC). Therefore, the aim of the present study was to identify how SchA functioned to affect the progression of GC. To investigate the role of SchA in GC development, Cell Counting Kit‑8, colony formation, wound healing and Transwell assays were conducted to assess the viability, proliferation, migration and invasion of AGS cells, respectively. Then, the apoptosis rate and apoptosis‑ and endoplasmic reticulum (ER) stress‑related protein expression levels in AGS cells exposed to SchA were detected via TUNEL assays and western blotting, respectively. Subsequently, the aforementioned functional assays were performed again in AGS cells exposed to both SchA and the ER stress inhibitor 4‑phenylbutyric acid (4‑PBA) for the confirmation of the effect of SchA on ER stress in GC. It was found that SchA markedly decreased the viability, proliferation, migration and invasion, while it induced the apoptosis of AGS cells. Moreover, the markers of ER stress were elevated by SchA treatment in AGS cells. Nevertheless, 4‑PBA reversed the effects of SchA on the viability, proliferation, migration, invasion and apoptosis of AGS cells, accompanied by decreased expression of ER stress markers. In conclusion, the present study demonstrated that SchA induced the apoptosis and suppressed the proliferation, invasion and migration of GC cells by activating ER stress, which provides a theoretical basis for the use of SchA in the treatment of GC.

Keywords:  endoplasmic reticulum stress; gastric cancer cells; invasion and migration; proliferation; schizandrin A

DOI:  https://doi.org/10.3892/mmr.2021.12427
Molecules. 2021 Sep 04. pii: 5386. [Epub ahead of print]26(17):

Bypassing the Resistance Mechanisms of the Tumor Ecosystem by Targeting the Endoplasmic Reticulum Stress Pathway Using Ruthenium- and Osmium-Based Organometallic Compounds: An Exciting Long-Term Collaboration with Dr. Michel Pfeffer.

Christian Gaiddon, Isabelle Gross, Xiangjun Meng, Marjorie Sidhoum, Georg Mellitzer, Benoit Romain, Jean-Batiste Delhorme, Aïna Venkatasamy, Alain C Jung, Michel Pfeffer.

  Metal complexes have been used to treat cancer since the discovery of cisplatin and its interaction with DNA in the 1960's. Facing the resistance mechanisms against platinum salts and their side effects, safer therapeutic approaches have been sought through other metals, including ruthenium. In the early 2000s, Michel Pfeffer and his collaborators started to investigate the biological activity of organo-ruthenium/osmium complexes, demonstrating their ability to interfere with the activity of purified redox enzymes. Then, they discovered that these organo-ruthenium/osmium complexes could act independently of DNA damage and bypass the requirement for the tumor suppressor gene TP53 to induce the endoplasmic reticulum (ER) stress pathway, which is an original cell death pathway. They showed that other types of ruthenium complexes-as well complexes with other metals (osmium, iron, platinum)-can induce this pathway as well. They also demonstrated that ruthenium complexes accumulate in the ER after entering the cell using passive and active mechanisms. These particular physico-chemical properties of the organometallic complexes designed by Dr. Pfeffer contribute to their ability to reduce tumor growth and angiogenesis. Taken together, the pioneering work of Dr. Michel Pfeffer over his career provides us with a legacy that we have yet to fully embrace.

Keywords:  ER stress pathway; TP53; cancer; cell death; chemotherapy; cisplatin; immunotherapy; osmium; photodynamic therapy; resistance; ruthenium

DOI:  https://doi.org/10.3390/molecules26175386
Biol Res. 2021 Sep 06. 54(1): 27

Demethylzeylasteral (T-96) initiates extrinsic apoptosis against prostate cancer cells by inducing ROS-mediated ER stress and suppressing autophagic flux.

Dong-Lin Yang, Ya-Jun Zhang, Liu-Jun He, Chun-Sheng Hu, Li-Xia Gao, Jiu-Hong Huang, Yan Tang, Jie Luo, Dian-Yong Tang, Zhong-Zhu Chen.

   BACKGROUND: Demethylzeylasteral (T-96) is a pharmacologically active triterpenoid monomer extracted from Tripterygium wilfordii Hook F (TWHF) that has been reported to exhibit anti-neoplastic effects against several types of cancer cells. However, the potential anti-tumour effects of T-96 against human Prostate cancer (CaP) cells and the possible underlying mechanisms have not been well studied.
RESULTS: In the current study, T-96 exerted significant cytotoxicity to CaP cells in vitro and induced cell cycle arrest at S-phase in a dose-dependent manner. Mechanistically, T-96 promoted the initiation of autophagy but inhibited autophagic flux by inducing ROS-mediated endoplasmic reticulum (ER) stress which subsequently activated the extrinsic apoptosis pathway in CaP cells. These findings implied that T-96-induced ER stress activated the caspase-dependent apoptosis pathway to inhibit proliferation of CaP cells. Moreover, we observed that T-96 enhances the sensitivity of CaP cells to the chemotherapeutic drug, cisplatin.
CONCLUSIONS: Taken together, our data demonstrated that T-96 is a novel modulator of ER stress and autophagy, and has potential therapeutic applications against CaP in the clinic.

Keywords:  Apoptosis; Autophagic flux; CaP; Cisplatin; ER stress; T-96

DOI:  https://doi.org/10.1186/s40659-021-00350-6
J Food Sci. 2021 Sep 07.

Docosahexaenoic acid monoglyceride induces apoptosis and autophagy in breast cancer cells via lipid peroxidation-mediated endoplasmic reticulum stress.

Tian-Tian Wang, Yong Yang, Feng Wang, Wen-Ge Yang, Jin-Jie Zhang, Zu-Quan Zou.

  Epidemiologic and preclinical studieshave shown that marine n-3 polyunsaturated fatty acids (n-3 PUFAs) elicit promising chemoprevention against breast cancer. Docosahexaenoic acid monoglyceride (MAG-DHA), a docosahexaenoic acid sn-1-monoacylglycerol does not required pancreatic lipase to be absorbed, eliciting a better bioavailability when compared with other formulations such as DHA-free fatty acid, DHA-triglycerol, or DHA-ethyl ester. However, the anticancer actions and underlying mechanisms of MAG-DHA on breast cancer remain to be assessed. In this study, MAG-DHA induced significant growth inhibition in MCF-7 and MDA-MB-231 breast cancer cells in a dose-dependent manner. MAG-DHA treatment (80 µM) led to 83.8 and 94.3% growth inhibition between MCF-7 and MDA-MB-231 cells, respectively. MAG-DHA-induced growth inhibition was tightly associated with apoptosis, as evidenced by increased active forms of caspase-3, poly (ADP-ribose) polymerase (PARP) and caspase-12. In particular, MAG-DHA-induced apoptosis was triggered by oxidative stress-mediated endoplasmic reticulum (ER) stress, as evidenced by activation of the PERK-eIF2α pathway in ER. MAG-DHA treatment also strongly suppressed the growth of E0771 murine breast cancer xenografts, significant differences of tumor volume were found between MAG-DHA group (0.271 cm3 ) and control group (0.875 cm3 ) after 15 daily MAG-DHA treatments. The in vitro antibreast cancer mechanism of MAG-DHA was supported by the in vivo xenograft model. In addition, MAG-DHA-induced ER stress concomitantly triggered autophagy in these cancer cells, and the induction of autophagy suppressed its ability to induce apoptotic cell death. Our data suggested that MAG-DHA as dietary supplement, in combination with autophagy inhibitors may be a useful therapeutic strategy in treating breast cancer.

Keywords:  MAG-DHA; apoptosis; autophagy; breast cancer; endoplasmic reticulum stress; lipid peroxidation

DOI:  https://doi.org/10.1111/1750-3841.15900
Phytomedicine. 2021 Aug 19. pii: S0944-7113(21)00266-X. [Epub ahead of print]92 153723

Pristimerin induces apoptosis and tumor inhibition of oral squamous cell carcinoma through activating ROS-dependent ER stress/Noxa pathway.

Qun Zhao, Xinran Cheng, Wei Yu, Yun Bi, Jian Guo, Qingzhao Ma, Yingxia Gong, Li He, Xianjun Yu.

   BACKGROUND: Pristimerin (Pri), a natural quinone methide triterpenoid isolated from Celastraceae and Hippocrateaceae, exhibits potent antitumor activity against various cancers. However, the mechanism of apoptosis induction by Pri in oral squamous cell carcinoma (OSCC) and its anti-OSCC effect in vivo has not been widely studied.
PURPOSE: This study aimed to investigate the anti-OSCC activities of Pri in vitro and in vivo and addressed the potential mechanisms of Pri-induced apoptosis.
METHODS: The effects of Pri on OSCC cells were analyzed by cell viability, colony formation and flow cytometry assays. Western blotting and qRT-PCR assays were chosen to detect the expression of proteins and genes. The anti-OSCC efficacy of Pri in vivo was evaluated by CAL-27 xenografts.
RESULTS: We showed that Pri inhibited the proliferation of human OSCC cell lines. Additionally, Pri induced apoptosis by upregulating Noxa expression. Furthermore, Pri treatment triggered excessive endoplasmic reticulum (ER) stress activation and subsequently induced c-Jun N-terminal kinase (JNK) signaling. ROS scavengers and ER stress inhibitors significantly attenuated Pri-induced OSCC cell apoptosis. Finally, Pri suppressed tumor growth in CAL-27 xenografts, accompanied ER stress activation and cell apoptosis.
CONCLUSION: These results reveal that Pri suppressed tumor growth and triggered cell apoptosis through ER stress activation in OSCC cells and xenografts, suggesting that Pri may serve as a therapeutic agent for OSCC.

Keywords:  Apoptosis; ER stress; Noxa; OSCC; Pri

DOI:  https://doi.org/10.1016/j.phymed.2021.153723
Nat Commun. 2021 Sep 07. 12(1): 5321

Targeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer.

Jianhuang Lin, Heng Liu, Takeshi Fukumoto, Joseph Zundell, Qingqing Yan, Chih-Hang Anthony Tang, Shuai Wu, Wei Zhou, Dajiang Guo, Sergey Karakashev, Chih-Chi Andrew Hu, Kavitha Sarma, Andrew V Kossenkov, Rugang Zhang.

CARM1 is often overexpressed in human cancers including in ovarian cancer. However, therapeutic approaches based on CARM1 expression remain to be an unmet need. Cancer cells exploit adaptive responses such as the endoplasmic reticulum (ER) stress response for their survival through activating pathways such as the IRE1α/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1α/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1α/XBP1s pathway was effective against ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model. Our data show that pharmacological inhibition of the IRE1α/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.

DOI: https://doi.org/10.1038/s41467-021-25684-3
Cancers (Basel). 2021 Aug 26. pii: 4290. [Epub ahead of print]13(17):

The Novel Antitumor Compound HCA Promotes Glioma Cell Death by Inducing Endoplasmic Reticulum Stress and Autophagy.

Roberto Beteta-Göbel, Javier Fernández-Díaz, Laura Arbona-González, Raquel Rodríguez-Lorca, Manuel Torres, Xavier Busquets, Paula Fernández-García, Pablo V Escribá, Victoria Lladó.

  Glioblastoma (GBM) is the most common and aggressive type of primary brain tumor in adults, and the median survival of patients with GBM is 14.5 months. Melitherapy is an innovative therapeutic approach to treat different diseases, including cancer, and it is based on the regulation of cell membrane composition and structure, which modulates relevant signal pathways. Here, we have tested the effects of 2-hydroxycervonic acid (HCA) on GBM cells and xenograft tumors. HCA was taken up by cells and it compromised the survival of several human GBM cell lines in vitro, as well as the in vivo growth of xenograft tumors (mice) derived from these cells. HCA appeared to enhance ER stress/UPR signaling, which consequently induced autophagic cell death of the GBM tumor cells. This negative effect of HCA on GBM cells may be mediated by the JNK/c-Jun/CHOP/BiP axis, and it also seems to be provoked by the cellular metabolite of HCA, C21:5n-3 (heneicosapentaenoic acid). These results demonstrate the efficacy of the melitherapeutic treatment used and the potential of using C21:5n-3 as an efficacy biomarker for this treatment. Given the safety profile in animal models, the data presented here provide evidence that HCA warrants further clinical study as a potential therapy for GBM, currently an important unmet medical need.

Keywords:  ER stress; HCA; autophagy; glioma; membrane lipid therapy

DOI:  https://doi.org/10.3390/cancers13174290
Acta Biochim Biophys Sin (Shanghai). 2021 Sep 08. pii: gmab115. [Epub ahead of print]

Targeting GRP78 enhances the sensitivity of HOS osteosarcoma cells to pyropheophorbide-α methyl ester-mediated photodynamic therapy via the Wnt/β-catenin signaling pathway.

Qiang Zuo, Yunsheng Ou, Shenxi Zhong, Haoyang Yu, Fangbiao Zhan, Muzi Zhang.

  Photodynamic therapy (PDT), which is a new method for treating tumors, has been used in the treatment of cancer. In-depth research has shown that PDT cannot completely kill tumor cells, indicating that tumor cells are resistant to PDT. Glucose regulatory protein 78 (GRP78), which is a key regulator of endoplasmic reticulum stress, has been confirmed to be related to tumor resistance and recurrence, but there are relatively few studies on the further mechanism of GRP78 in PDT. Our experiment aimed to observe the role of GRP78 in HOS human osteosarcoma cells treated with pyropheophorbide-α methyl ester-mediated photodynamic therapy (MPPα-PDT) and to explore the possible mechanism by which the silencing of GRP78 expression enhances the sensitivity of HOS osteosarcoma cells to MPPα-PDT. HOS osteosarcoma cells were transfected with siRNA-GRP78. Apoptosis and reactive oxygen species (ROS) levels were detected by Hoechst staining and flow cytometry, cell viability was detected by Cell Counting Kit-8 assay, GRP78 protein fluorescence intensity was detected by immunofluorescence, and apoptosis-related proteins, cell proliferation-related proteins, and Wnt pathway-related proteins were detected by western blot. The results showed that MPPα-PDT can induce HOS cell apoptosis and increase GRP78 expression. After successful siRNA-GRP78 transfection, HOS cell proliferation was decreased, and apoptosis-related proteins expressions was increased, Wnt/β-catenin-related proteins expressions was decreased, and ROS levels was increased. In summary, siRNA-GRP78 enhances the sensitivity of HOS cells to MPPα-PDT, the mechanism may be related to inhibiting Wnt pathway activation and increasing ROS levels.

Keywords:  Wnt signaling pathway; glucose regulated protein 78; osteosarcoma; photodynamic therapy; pyropheophorbide-α methyl ester; reactive oxygen species

DOI:  https://doi.org/10.1093/abbs/gmab115
Int J Mol Sci. 2021 Aug 30. pii: 9405. [Epub ahead of print]22(17):

The Role of ER Stress-Related Phenomena in the Biology of Malignant Peripheral Nerve Sheath Tumors.

Anna Walczak, Maciej Radek, Ireneusz Majsterek.

  Malignant peripheral nerve sheath tumors (MPNST) are rare but one of the most aggressive types of cancer. Currently, there are no effective chemotherapy strategies for these malignancies. The inactivation of the neurofibromatosis type I (NF1) gene, followed by loss of TP53, is an early stage in MPNST carcinogenesis. NF1 is a negative regulator of the Ras proteins family, which are key factors in regulating cell growth, homeostasis and survival. Cell cycle dysregulation induces a stress phenotype, such as proteotoxic stress, metabolic stress, and oxidative stress, which should result in cell death. However, in the case of neoplastic cells, we observe not only the avoidance of apoptosis, but also the impact of stress factors on the treatment effectiveness. This review focuses on the pathomechanisms underlying MPNST cells physiology, and discusses the possible ways to develop a successful treatment based on the molecular background of the disease.

Keywords:  ER-stress; MPNST; UPR

DOI:  https://doi.org/10.3390/ijms22179405