bims-istrec Biomed News
on Integrated stress response in cancer
Issue of 2022‒07‒03
seven papers selected by
the Vincenzo Ciminale lab
Istituto Oncologico Veneto

  1. Environ Toxicol Pharmacol. 2022 Jun 23. pii: S1382-6689(22)00112-0. [Epub ahead of print] 103919
      Tebuconazole (TEB) is a common triazole fungicide that has been widely applied in the treatment of fungal diseases. It is reported that TEB could exert harmful effects on mammals' health. However, the molecular mechanism involved in TEB toxicity remain undefined. Our study aimed to investigate the mechanisms of TEB-induced toxicity in intestinal cells. We found that TEB stimulates apoptosis through the mitochondrial pathway. Additionally, TEB triggers endoplasmic reticulum (ER) stress as demonstrated by the activation of the three arms of unfolded protein response (UPR). The incubation with the chemical chaperone 4-phenylbutyrate (4-PBA) alleviated ER stress and reduced TEB-induced apoptosis, suggesting that ER stress plays an important role in mediating TEB-induced toxicity. Furthermore, inhibition of ROS by N-acetylcysteine (NAC) inhibited TEB-induced ER stress and apoptosis. Taken together, these findings suggest that TEB exerts its toxic effects in HCT116 cells by inducing apoptosis through ROS-mediated ER stress and mitochondrial apoptotic pathway.
    Keywords:  Apoptosis; Endoplasmic Reticulum Stress; ROS; Tebuconazole
  2. Korean J Anesthesiol. 2022 Jun 28.
      Background: Numerous studies suggest a benefit of the use of intravenous propofol over inhalational volatile anesthetic. The objective of this study was to compare the changes in endoplasmic reticulum (ER) stress of cancer cells and lymphocytes after propofol- or sevoflurane-based anesthesia during breast cancer surgery.Methods: A total of 53 patients having breast cancer surgery were randomized and analyzed (28 for propofol, 25 for sevoflurane). Blood samples were obtained immediately before anesthesia induction, and 1 and 24 hours postoperatively. Human breast cancer cell lines were cultured and then treated with patients' plasma and the frequency of C/EBP homologous protein (CHOP) on cancer cell lines and lymphocytes were measured. The neutrophil-to-lymphocyte ratio in plasma was also evaluated in both groups.
    Results: The expressions of CHOP of breast cancer cell lines in both groups did not show significant intergroup differences between the two groups (P = 0.108). However, they significantly decreased over time (P = 0.027). The expressions of CHOP on lymphocytes were comparable between the two groups (P = 0.485), and the neutrophil to lymphocyte ratio did not significantly differ between the two groups (P = 0.501).
    Conclusions: Propofol-based anesthesia did not induce higher ER stress rather than sevoflurane-based anesthesia during breast cancer surgery. The types of anesthetics during breast cancer surgery did not have different effect on ER stress of cancer cells.
    Keywords:  Apoptosis; Breast Cancer; Endoplasmic reticulum; Propofol; Sevoflurane
  3. Elife. 2022 Jun 27. pii: e77780. [Epub ahead of print]11
      Cells encountering stressful situations activate the integrated stress response (ISR) pathway to limit protein synthesis and redirect translation to better cope. The ISR has also been implicated in cancers, but redundancies in the stress-sensing kinases that trigger the ISR have posed hurdles to dissecting physiological relevance. To overcome this challenge, we targeted the regulatory node of these kinases, namely the S51 phosphorylation site of eukaryotic translation initiation factor eIF2α and genetically replaced eIF2α with eIF2α-S51A in mouse squamous cell carcinoma (SCC) stem cells of skin. While inconsequential under normal growth conditions, the vulnerability of this ISR-null state was unveiled when SCC stem cells experienced proteotoxic stress. Seeking mechanistic insights into the protective roles of the ISR, we combined ribosome profiling and functional approaches to identify and probe the functional importance of translational differences between ISR-competent and ISR-null SCC stem cells when exposed to proteotoxic stress. In doing so, we learned that the ISR redirects translation to centrosomal proteins that orchestrate the microtubule dynamics needed to efficiently concentrate unfolded proteins at the microtubule organizing center so that they can be cleared by the perinuclear degradation machinery. Thus, rather than merely maintaining survival during proteotoxic stress, the ISR also functions in promoting cellular recovery once the stress has subsided. Remarkably, this molecular program is unique to transformed skin stem cells hence exposing a vulnerability in cancer that could be exploited therapeutically.
    Keywords:  cancer biology; cell biology; mouse
  4. Evid Based Complement Alternat Med. 2022 ;2022 6886366
      Objective: Non-small-cell lung cancer (NSCLC) is one of the most lethal cancers. Although cisplatin-based chemotherapies have been regarded as a promising treatment approach, cisplatin resistance still remains one of the major clinical challenges. Curcumin, a naturally occurring polyphenol, has been proved to increase chemotherapeutic efficiency of NSCLC cells. However, the role of curcumin in cisplatin-resistant NSCLC cells has been rarely investigated. This study aims to investigate whether curcumin enhances cisplatin sensitivity of human NSCLC cells and its underlying mechanisms.Method: A549/DDP and H1299/DDP cells were treated by DDP or/and curcumin before cell viability, and apoptosis were determined by using a CCK-8 assay and flow cytometer. The expressions of apoptosis and ER stress-related proteins, including cleaved caspase-3, cleaved PARP, CHOP, GRP78, XBP-1, ATF6, and caspase-4, were measured by the qPCR and western blotting. After cotreatment by DDP and curcumin, A549/DDP and H1299/DDP cells were further treated by the ER stress inhibitor, salubrinal (20 μm), after which the cell apoptosis and viability were detected.
    Result: Treatment by DDP and curcumin can substantially decrease cell viability, while can increase the cell apoptosis rate, elevate mRNA and protein expressions of apoptosis and ER stress-related proteins, compared with cells treated by DDP or curcumin alone. Salubrinal treatment can counteract the suppressive effect of DDP and curcumin on cell viability and decrease the cell apoptosis of A549/DDP and H1299/DDP cells.
    Conclusion: Curcumin can increase the sensitivity of NSCLC to cisplatin through an ER stress pathway and thus can be served as one of the molecular targets for overcoming the cisplatin resistance.
  5. Adv Sci (Weinh). 2022 Jun 26. e2201819
      Specific localization of photosensitizers (PSs) to a certain organelle could result in targeted attack to cause greater trauma to cancer cells, eventually maximizing photodynamic therapy (PDT). However, currently, efficient and precise transportation of PSs via drug delivery to tumor cells and subcellular organelles is still challenging, due to a so-called step-reduction delivery dilemma (SRDD) which also threatens anticancer drug delivery to exert their efficacy. Herein, a cascade targeting near infrared II (NIR II) fluorescent nanoparticles (NPER/BO-PDT ) is designed that can target bone tumor first and then target the subcellular organelle of endoplasmic reticulum (ER). It is found that NPER/BO-PDT achieves the targeted accumulation of the bone tumor and then ER. NPER/BO-PDT generates reactive oxygen species (ROS) in the subcellular organelles of ER under near infrared light irradiation. The continuous ER stress by ROS promotes the release of more damage-associated molecular patterns, induces immunogenic cell death, stimulates the adaptive immune response, and further synergistically inhibits tumor growth, achieving the so-called photodynamic-immunotherapy. Overall, this study exemplifies a safe and efficient nano-drug delivery system for a bone and ER cascade targeting via delivery of PSs to break the SRDD and highlights potential clinical translation.
    Keywords:  cascade targeting; endoplasmic reticulum stress; photodynamic-immunotherapy; step-reduction delivery dilemma
  6. Anal Chem. 2022 Jun 30.
      CYP2J2 as an endoplasmic reticulum (ER)-expressed vital cytochrome P450 isoform participates in the metabolism of endogenous polyunsaturated fatty acids. Its abnormal expression and function are closely related to the progress of cancer and cardiovascular diseases. Herein, an ER-targeting near-infrared (NIR) fluorescent probe ER-BnXPI was developed for monitoring CYP2J2 activity, which possessed a high selectivity and sensitivity toward CYP2J2 among various CYP450 isoforms and exhibited excellent subcellular localization for ER. Then, the CYP2J2 variation behavior under the ER stress model was imaged by ER-BnXPI in living cells and successfully used for the in vivo imaging in different tumors that well distinguished tumor tissues from para-cancerous tissues. All these findings fully demonstrated that ER-BnXPI could be used as a promising tool for exploring the physiological function of CYP2J2 and provided some novel approach for the diagnosis and therapy of CYP2J2-related vascular inflammation and cancer.