ABSTRACT
Colorectal cancer (CRC) is the second most deadly cancer worldwide. Although various treatments for CRC have made progress, they have limitations. Therefore, the search for new effective molecular targets is important for the treatment of CRC. p20BAP31 induces apoptosis through diverse pathways and exhibits greater sensitivity in CRC. Therefore, a comprehensive exploration of the molecular functions of p20BAP31 is important for its application in anti-tumor therapy. In this study, we showed that exogenous p20BAP31 was still located in the ER and significantly activated the unfolded protein response (UPR) through the PERK pathway. The activation of the PERK pathway is prominent in p20BAP31-induced reactive oxygen species (ROS) accumulation and apoptosis. We found, for the first time, that p20BAP31 leads to ER stress and markedly attenuates tumor cell growth in vivo. Importantly, mechanistic investigations indicated that p20BAP31 competitively binds to GRP78 from PERK and causes hyperactivation of the UPR. Furthermore, p20BAP31 upregulates the expression of GRP78 by promoting HSF1 nuclear translocation and enhancing its binding to the GRP78 promoter. These findings reveal p20BAP31 as a regulator of ER stress and a potential target for tumor therapy, and elucidate the underlying mechanism by which p20BAP31 mediates signal transduction between ER and mitochondria.
Subject(s)
Apoptosis , Colorectal Neoplasms , Endoplasmic Reticulum Chaperone BiP , Endoplasmic Reticulum Stress , Heat-Shock Proteins , Reactive Oxygen Species , Signal Transduction , Unfolded Protein Response , eIF-2 Kinase , Humans , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Colorectal Neoplasms/genetics , Apoptosis/drug effects , eIF-2 Kinase/metabolism , eIF-2 Kinase/genetics , Heat-Shock Proteins/metabolism , Heat-Shock Proteins/genetics , Animals , Cell Line, Tumor , Reactive Oxygen Species/metabolism , Mice , Cell Proliferation , Protein Binding , Gene Expression Regulation, NeoplasticABSTRACT
B-cell receptor-associated protein 31 (BAP31) is an endoplasmic reticulum (ER) membrane protein involved in apoptosis and autophagy by communication with ER and mitochondria. BAP31 is cleaved by caspase-8 and generates a proapoptotic fragment, p20BAP31, which has shown to induce ER stress and apoptosis through multiple pathways. In this study, we found that p20BAP31 significantly increased the agglomeration of LC3 puncta, suggesting the occurrence of autophagy. Therefore, it is meaningful to explore the mechanism of p20BAP31-induced autophagy, and further analyze the relationships among p20BAP31-induced autophagy, ER stress and apoptosis. The data showed that p20BAP31 induced autophagy by inhibition of the PI3K/AKT/mTOR signaling in colorectal cells. ER stress inhibitor 4-PBA and PERK siRNA alleviated p20BAP31-induced autophagy; in turn, autophagy inhibitors 3-MA and CQ did not affect p20BAP31-induced ER stress, suggesting that p20BAP31-induced ER stress is the upstream of autophagy. We also discovered that ROS inhibitor NAC inhibited p20BAP31-induced autophagy. Furthermore, inhibition of autophagy by CQ suppressed p20BAP31-induced apoptosis and ameliorated cell proliferation. Importantly, p20BAP31 markedly reduced the tumor size in vivo, and significantly enhanced the autophagy levels in the tumor tissues. Collectively, p20BAP31 initiates autophagy by inhibiting the PI3K/AKT/mTOR signaling and activating the PERK-mediated ROS accumulation, further promotes p20BAP31-induced apoptosis and ultimately results in cell death. This study comprehensively reveals the potential mechanism of p20BAP31-induced cell death, which may provide new strategies for antitumor therapy.
Subject(s)
Apoptosis , Autophagy , Colorectal Neoplasms , Endoplasmic Reticulum Stress , Signal Transduction , eIF-2 Kinase , Endoplasmic Reticulum Stress/drug effects , Autophagy/drug effects , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Colorectal Neoplasms/genetics , Humans , eIF-2 Kinase/metabolism , eIF-2 Kinase/genetics , Animals , Mice , Signal Transduction/drug effects , Apoptosis/drug effects , Cell Line, Tumor , TOR Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Mice, Nude , Membrane Proteins/metabolism , Membrane Proteins/geneticsABSTRACT
A reduced graphene oxide encapsulating Fe6Ni20Co2Mn2Cu1.5@rGO catalyst is prepared using a Joule heating strategy. The graphene-coated layer with high crystallinity enhances the stability of the crystal structure, resulting in superior OER activity. Rechargeable zinc-air batteries with Fe6Ni20Co2Mn2Cu1.5@rGO demonstrate remarkable performance, boasting a high specific capacity of 800 mA h gZn-1, an impressive peak power density of 154.612 mW cm-2, and a cycle life of 300 hours at a current density of 10 mA cm-2.
ABSTRACT
A H2SO4-Ti3C2Tx ion-gel is in situ fabricated to prevent the restacking of Ti3C2Tx for high-rate micro-supercapacitors. The ion-gel pillared by an electrolyte possesses an enlarged interlayer spacing facilitating ion transport. Furthermore, a bilayer structure is designed with dry Ti3C2Tx for fast electron conduction. The bilayer Ti3C2Tx film shows improved capacitance from 49% to 73% of the initial capacitance at a high scan rate of 200 mV s-1, along with excellent cycle stability. This study opens up a concise and efficient way for high-performance micro-supercapacitors.
ABSTRACT
Shiga toxin-producing Escherichia coli(STEC) O157: H7 strains were isolated from domestic animals and patients from Xuzhou City, Jiangsu Province, China and the bordering Anhui and Henan Provinces and were examined for the stx genotype. Of 390 strains, 277 were identified as genotype stx2vha ; 41, stx2 ; 51, stx2-stx1 ; 1, stx2-stx2vha-stx1 ; 5, stx2-stx2vha ; and 15 were un-typeable. Of the 277 stx2vha-bearing isolates, 116 were isolated from goats; 42, cattle; 38, hens, and 35 from pigs. The study shows stx2vha is the dominant genotype and goats are an important reservoir.
