Loss of p53 enhances the function of the endoplasmic reticulum through activation of the IRE1α/XBP1 pathway

Altered regulation of ER stress response has been implicated in a variety of human diseases, such as cancer and metabolic diseases. Excessive ER function contributes to malignant phenotypes, such as chemoresistance and metastasis. Here we report that the tumor suppressor p53 regulates ER function in response to stress. We found that loss of p53 function activates the IRE1α/XBP1 pathway to enhance protein folding and secretion through upregulation of IRE1α and subsequent activation of its target XBP1. We also show that wild-type p53 interacts with synoviolin (SYVN1)/HRD1/DER3, a transmembrane E3 ubiquitin ligase localized to ER during ER stress and removes unfolded proteins by reversing transport to the cytosol from the ER, and its interaction stimulates IRE1α degradation. Moreover, IRE1α inhibitor suppressed protein secretion, induced cell death in p53-deficient cells, and strongly suppressed the formation of tumors by p53-deficient human tumor cells in vivo compared with those that expressed wild-type p53. Therefore, our data imply that the IRE1α/XBP1 pathway serves as a target for therapy of chemoresistant tumors that express mutant p53

Synthetic lethality by targeting the RUVBL1/2-TTT complex in mTORC1-hyperactive cancer cells

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.Despite considerable efforts, mTOR inhibitors have produced limited success in the clinic. To define the vulnerabilities of mTORC1-addicted cancer cells and to find previously unknown therapeutic targets, we investigated the mechanism of piperlongumine, a small molecule identified in a chemical library screen to specifically target cancer cells with a hyperactive mTORC1 phenotype. Sensitivity to piperlongumine was dependent on its ability to suppress RUVBL1/2-TTT, a complex involved in chromatin remodeling and DNA repair. Cancer cells with high mTORC1 activity are subjected to higher levels of DNA damage stress via c-Myc and displayed an increased dependency on RUVBL1/2 for survival and counteracting genotoxic stress. Examination of clinical cancer tissues also demonstrated that high mTORC1 activity was accompanied by high RUVBL2 expression. Our findings reveal a previously unknown role for RUVBL1/2 in cell survival, where it acts as a functional chaperone to mitigate stress levels induced in the mTORC1-Myc-DNA damage axis.NIH 1RO1CA142805National Research Foundation of Korea (NRF) grant (NRF-2017R1C1B1006072

Therapeutic Implications of Autophagy Inducers in Immunological Disorders, Infection, and Cancer

Autophagy is an essential catabolic program that forms part of the stress response and enables cells to break down their own intracellular components within lysosomes for recycling. Accumulating evidence suggests that autophagy plays vital roles in determining pathological outcomes of immune responses and tumorigenesis. Autophagy regulates innate and adaptive immunity affecting the pathologies of infectious, inflammatory, and autoimmune diseases. In cancer, autophagy appears to play distinct roles depending on the context of the malignancy by either promoting or suppressing key determinants of cancer cell survival. This review covers recent developments in the understanding of autophagy and discusses potential therapeutic interventions that may alter the outcomes of certain diseases

Anti-Atopic Dermatitis Activity of Cornus walteri and Identification of the Bioactive Compounds

Atopic dermatitis (AD) is a chronic inflammatory disease characterized by hyperactivated immune reactions in the skin. AD is a prevalent health concern in developing countries, with a particularly high incidence among children. Despite ongoing research on AD, prevention and treatment strategies for patients remain inadequate. In this study, the inhibitory effects of Cornus walteri on AD were investigated. C. walteri (Cornaceae), commonly known as “Walter’s dogwood,” is a deciduous shrub used as a traditional medicine to treat dermatologic inflammation caused by lacquer poisoning. However, the role of C. walteri in AD remains largely unknown. To evaluate its anti-AD potential, we investigated the anti-inflammatory activity of the MeOH extract of C. walteri stems (CWS) using the HaCaT human keratinocyte cell line. CWS reduced the secretion of AD-related chemokines, eotaxin-3/CCL26 and thymus and activation-regulated chemokine (TARC/CCL17). In addition, CWS also inhibited the mRNA expression of macrophage-derived chemokine (MDC/CCL22) and upregulated filaggrin, which plays an essential role in skin barrier functions. To identify the bioactive constituents of CWS, phytochemical investigation of CWS led to the isolation of potential bioactive constituents (1–6), including four triterpenoids, one steroid and one diterpene analog, the structures of which were identified as lupeol (1), betulinic acid (2), 5α-stigmast-3,6-dione (3), 3-O-acetylbetulin (4), betulinic acid methyl ester (5) and norphytan (6) through nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography (LC)–mass spectrometry (MS) analysis. The isolated compounds (1–6) were evaluated for their inhibitory activities against eotaxin-3 expression. Compounds 1, 2 and 3 significantly reduced the levels of eotaxin-3. These findings provided experimental evidence that CWS, particularly active compounds 1, 2 and 3, could be further utilized as potential therapeutic agents to treat AD

Anti-Atopic Dermatitis Activity of <i>Cornus walteri</i> and Identification of the Bioactive Compounds

Atopic dermatitis (AD) is a chronic inflammatory disease characterized by hyperactivated immune reactions in the skin. AD is a prevalent health concern in developing countries, with a particularly high incidence among children. Despite ongoing research on AD, prevention and treatment strategies for patients remain inadequate. In this study, the inhibitory effects of Cornus walteri on AD were investigated. C. walteri (Cornaceae), commonly known as “Walter’s dogwood,” is a deciduous shrub used as a traditional medicine to treat dermatologic inflammation caused by lacquer poisoning. However, the role of C. walteri in AD remains largely unknown. To evaluate its anti-AD potential, we investigated the anti-inflammatory activity of the MeOH extract of C. walteri stems (CWS) using the HaCaT human keratinocyte cell line. CWS reduced the secretion of AD-related chemokines, eotaxin-3/CCL26 and thymus and activation-regulated chemokine (TARC/CCL17). In addition, CWS also inhibited the mRNA expression of macrophage-derived chemokine (MDC/CCL22) and upregulated filaggrin, which plays an essential role in skin barrier functions. To identify the bioactive constituents of CWS, phytochemical investigation of CWS led to the isolation of potential bioactive constituents (1–6), including four triterpenoids, one steroid and one diterpene analog, the structures of which were identified as lupeol (1), betulinic acid (2), 5α-stigmast-3,6-dione (3), 3-O-acetylbetulin (4), betulinic acid methyl ester (5) and norphytan (6) through nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography (LC)–mass spectrometry (MS) analysis. The isolated compounds (1–6) were evaluated for their inhibitory activities against eotaxin-3 expression. Compounds 1, 2 and 3 significantly reduced the levels of eotaxin-3. These findings provided experimental evidence that CWS, particularly active compounds 1, 2 and 3, could be further utilized as potential therapeutic agents to treat AD