bims-istrec Biomed News
on Integrated stress response in cancer
Issue of 2021‒11‒07
four papers selected by
Vincenzo Ciminale’s Lab
Istituto Oncologico Veneto


  1. Bioengineered. 2021 Nov 01.
      Blockage of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signal pathway is effective to increase the cytotoxic effects of oncolytic virus on cancer cells, but the detailed mechanisms are still largely unknown. Based on this, the present study managed to investigate the anti-tumor effects of PI3K inhibitor ZSTK474 and oncolytic vesicular stomatitis virus VSVΔ51 combination treatments on osteosarcoma (OS) in vitro and in vivo. Specifically, ZSTK474 aggravated the inhibiting effects of VSVΔ51 on osteosarcoma development by triggering endoplasmic reticulum (ER)-stress mediated apoptotic cell death. Mechanistically, either ZSTK474 or VSVΔ51 alone had limited effects on cell viability in osteosarcoma cells, while ZSTK474 and VSVΔ51 combination treatments significantly induced osteosarcoma cell apoptosis. Interestingly, VSVΔ51 increased the expression levels of IRE1α and p-PERK to initiate ER stress in osteosarcoma cells, which were aggravated by co-treating cells with ZSTK474. Next, the promoting effects of ZSTK474-VSVΔ51 combined treatment on osteosarcoma cell death were abrogated by the ER-stress inhibitor 4-phenyl butyric acid (4-PBA), indicating that ZSTK474 enhanced the cytotoxic effects of VSVΔ51 on osteosarcoma cells in an ER-stress dependent manner. Finally, the xenograft tumor-bearing mice models were established, and the results showed that ZSTK474-VSVΔ51 combined treatment synergistically hindered tumorigenesis of osteosarcoma cells in vivo. Taken together, our data suggested that ZSTK474 was a novel agent to enhance the cytotoxic effects of VSVΔ51 on osteosarcoma by aggravating ER-stress, and the present study might provide alternative therapy treatments for osteosarcoma in clinic.
    Keywords:  Oncolytic virus; Osteosarcoma; PI3K inhibitor; VSVΔ51; ZSTK474
    DOI:  https://doi.org/10.1080/21655979.2021.1999372
  2. Cell Death Dis. 2021 Nov 01. 12(11): 1038
      Cancer cells experience endoplasmic reticulum (ER) stress due to activated oncogenes and conditions of nutrient deprivation and hypoxia. The ensuing unfolded protein response (UPR) is executed by ATF6, IRE1 and PERK pathways. Adaptation to mild ER stress promotes tumor cell survival and aggressiveness. Unmitigated ER stress, however, will result in cell death and is a potential avenue for cancer therapies. Because of this yin-yang nature of ER stress, it is imperative that we fully understand the mechanisms and dynamics of the UPR and its contribution to the complexity of tumor biology. The PERK pathway inhibits global protein synthesis while allowing translation of specific mRNAs, such as the ATF4 transcription factor. Using thapsigargin and tunicamycin to induce acute ER stress, we identified the transcription factor C/EBPδ (CEBPD) as a mediator of PERK signaling to secretion of tumor promoting chemokines. In melanoma and breast cancer cell lines, PERK mediated early induction of C/EBPδ through ATF4-independent pathways that involved at least in part Janus kinases and the STAT3 transcription factor. Transcriptional profiling revealed that C/EBPδ contributed to 20% of thapsigargin response genes including chaperones, components of ER-associated degradation, and apoptosis inhibitors. In addition, C/EBPδ supported the expression of the chemokines CXCL8 (IL-8) and CCL20, which are known for their tumor promoting and immunosuppressive properties. With a paradigm of short-term exposure to thapsigargin, which was sufficient to trigger prolonged activation of the UPR in cancer cells, we found that conditioned media from such cells induced cytokine expression in myeloid cells. In addition, activation of the CXCL8 receptor CXCR1 during thapsigargin exposure supported subsequent sphere formation by cancer cells. Taken together, these investigations elucidated a novel mechanism of ER stress-induced transmissible signals in tumor cells that may be particularly relevant in the context of pharmacological interventions.
    DOI:  https://doi.org/10.1038/s41419-021-04318-y
  3. Mol Cancer Res. 2021 Nov 02. pii: molcanres.0702.2021. [Epub ahead of print]
      The discovery of 17β-estradiol (E2)-induced apoptosis has clinical relevance. Mechanistically, E2 over activates nuclear estrogen receptor α (ERα) that results in stress responses. The unfolded protein response (UPR) is initiated by E2 in the endoplasmic reticulum after hours of treatment in endocrine-resistant breast cancer cells, thereby activating three UPR sensors-PRK-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6) with different functions. Specifically, PERK plays a critical role in induction of apoptosis while IRE1α and ATF6 are involved in the endoplasmic reticulum stress-associated degradation (ERAD) of PI3K/Akt/mTOR pathways. In addition to attenuating protein translation, PERK increases the DNA-binding activity of nuclear factor-κB (NF-κB) and subsequent tumor necrosis factor α (TNFα) expression. Additionally, PERK communicates with the mitochondria to regulate oxidative stress at mitochondria-associated endoplasmic reticulum membranes (MAMs). Furthermore, PERK is a component enriched in MAMs that interacts with multifunctional MAM-tethering proteins and integrally modulates the exchange of metabolites such as lipids, reactive oxygen species (ROS), and Ca2+ at contact sites. MAMs are also critical sites for the initiation of autophagy to remove defective organelles and misfolded proteins through specific regulatory proteins. Thus, PERK conveys signals from nucleus to these membrane-structured organelles that form an interconnected network to regulate E2-induced apoptosis. Herein, we address the mechanistic progress on how PERK acts as a multifunctional molecule to commit E2 to inducing apoptosis in endocrine-resistant breast cancer.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-21-0702
  4. Cell Biosci. 2021 Oct 30. 11(1): 186
      In modern research, mitochondria are considered a more crucial energy plant in cells. Mitochondrial dysfunction, including mitochondrial DNA (mtDNA) mutation and denatured protein accumulation, is a common feature of tumors. The dysfunctional mitochondria reprogram molecular metabolism and allow tumor cells to proliferate in the hostile microenvironment. One of the crucial signaling pathways of the mitochondrial dysfunction activation in the tumor cells is the retrograde signaling of mitochondria-nucleus interaction, mitochondrial unfolded protein response (UPRmt), which is initiated by accumulation of denatured protein and excess ROS production. In the process of UPRmt, various components are activitated to enhance the mitochondria-nucleus retrograde signaling to promote carcinoma progression, including hypoxia-inducible factor (HIF), activating transcription factor ATF-4, ATF-5, CHOP, AKT, AMPK. The retrograde signaling molecules of overexpression ATF-5, SIRT3, CREB, SOD1, SOD2, early growth response protein 1 (EGR1), ATF2, CCAAT/enhancer-binding protein-d, and CHOP also involved in the process. Targeted blockage of the UPRmt pathway could obviously inhibit tumor proliferation and metastasis. This review indicates the UPRmt pathways and its crucial role in targeted therapy of metastasis tumors.
    Keywords:  Cytosolic heat shock response (HSR); Hypoxia-inducible factor (HIF); Integrated stress response (ISR); Mitochondrial unfolded protein response UPRmt; Mitohormesis; Retrograde signaling
    DOI:  https://doi.org/10.1186/s13578-021-00696-0