Inhibition of ATF4-mediated elevation of both autophagy and AKT/mTOR was involved in antitumorigenic activity of curcumin.

Curcumin, a natural hydrophobic polyphenol, carries significant anticancer activity. The protein kinase B (AKT)/the mammalian target of the rapamycin (mTOR) pathway and autophagy are well known to be involved in carcinogenesis, and usually, inhibition of mTOR is the main reason to promote autophagy. In this study, however, autophagy and mTOR were found to be inhibited simultaneously by curcumin treatments, and both of them played an important role in the effect of curcumin on suppressing the growth of A549 cells. Tunicamycin (TM), the activator of Endoplasmic Reticulum (ER) stress, increased both autophagy and AKT/mTOR, while curcumin could significantly decrease TM-induced autophagy and AKT/mTOR. Furthermore, curcumin could inhibit TM-induced aerobic glycolysis in A549 cells, and decrease the level of cycle-related and migration-related proteins. Blocking activating transcription factor 4 (ATF4) by siRNA strongly reduced both the expression of autophagy-related proteins and AKT/mTOR. ChIP assay illustrated that ATF4 protein could bind to the promotor sequence of either ATG4B or AKT1. The transplantation tumor experiment showed that the weight and volume of the transplanted tumors were reduced significantly in the BALB/c mice subcutaneously injected with A549 cells treated with curcumin. Moreover, intranasal administration of curcumin decreased the protein level of autophagy, AKT/mTOR and ER stress in lung tissues of BALB/c mice. Taken together, our results demonstrated that inhibition of ER stress-dependent ATF4-mediated autophagy and AKT/mTOR pathway plays an important role in anticancer effect of curcumin.

Research status, challenges and future prospects of renewable synthetic fuel catalysts for CO2 photocatalytic reduction conversion.

In recent years, with global climate change, the utilization of carbon dioxide as a resource has become an important goal of human society to achieve carbon peaking and carbon neutrality. Among them, the catalytic conversion of carbon dioxide to generate renewable fuels has received great attention. As one of these methods, photocatalysis has its unique properties and mechanism, which can only rely on sunlight without inputting other energy. It is an emerging discipline with great development prospects. The core of photocatalysis lies in the development of photocatalysts with high activity, high selectivity, low cost, and high durability. This review first introduces the background and mechanism of photocatalysis, then introduces various types of photocatalysts based on different substrates, and analyzes the methods and mechanisms to improve the activity and selectivity of photocatalysts. Finally, combining the plasmon effect with photocatalysis, the review analyzes the promoting effect of the plasmon effect on the photocatalytic carbon dioxide synthesis of renewable fuels, which provides a new idea for it.

Autophagy induces mTOR-dependent glucose uptake and mTOR-independent lactate utilization in cadmium-treated A549 cells.

Cadmium (Cd) is a non-essential heavy metal with many harmful effects, especially tumorigenesis. Previously we established that autophagy-dependent increasing of glycolysis played an important role in Cd-induced cell growth and migration of A549 and HELF cells. In this study, we found Cd could induce autophagy and mTOR in A549 cells, HELF cells and in lung tissues of BALB/c mice. More interestingly, Cd-induced elevation of mTOR was autophagy-dependent and autophagy-induced cell growth and glycolysis was mTOR-dependent. However, in A549 cells, besides the above mTOR-dependent pathway, Cd-induced autophagy could directly induce PKM2 and LDHA independent of mTOR. Further study showed that only in A549 cells could autophagy other than mTOR enable Cd to increase MCT1 expression and MCT1 was involved in autophagy-induced PKM2 and LDHA. Sodium lactate added in the culture medium promoted Cd-induced cell growth of A549 cells, while had no effect on HELF cells. Finally, the effect of autophagy/MCT1/PKM2 pathway on lactate utilization to facilitate Cd-induced A549 cell growth was determined. Above all, we concluded that in HELF cells, autophagy induced mTOR-dependent glycolysis in which GLUT1 and HKII was elevated to promote glucose intake to accelerate cell growth. Whereas, in A549 cells, besides the above pathway to use glucose, autophagy could induce an mTOR-independent glycolysis pathway in which lactate could be used as fuel through autophagy-MCT1-PKM2 to escape glucose deficiency.

HMGA2 mediates Cr (VI)-induced metabolic reprogramming through binding to mitochondrial D-Loop region.

Hexavalent chromium [Cr (VI)] exists environmentally and occupationally. It has been shown to pose a carcinogenic hazard in certain occupations. This study was to investigate the role of high mobility group A2 (HMGA2) in Cr (VI)-induced metabolism reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis in A549 and HELF cells. First, knockdown of HMGA2 by siHMGA2 significantly attenuated Cr (VI)-reduced expression of OXPHOS-related proteins (COX IV and ND1) and mitochondrial mass, indicating that HMGA2 was involved in Cr (VI)-reduced OXPHOS. Overexpression of HMGA2 by transfection of HMGA2-DNA plasmids reduced the expression of COX IV, ND1 and mitochondrial mass, suggesting the negative role of HMGA2 in OXPHOS. Secondly, both CCCP, the inhibitor of mitochondrial function, and the ER stress inhibitor, 4-phenylbutyric acid (4-PBA), decreased the level of HMGA2, indicating that the interaction of mitochondrial dysfunction and ER stress resulted in Cr (VI)-induced HMGA2 expression. Further study demonstrated that ER stress/HMGA2 axis mediated the metabolism rewiring from OXPHOS to aerobic glycolysis. Notably, Cr (VI) induced the accumulation of HMGA2 proteins in mitochondria and ChIP assay demonstrated that HMGA2 proteins could bind to D-loop region of mitochondrial DNA (mtDNA), which provided the proof for HMGA2-modulating OXPHOS. Taken together, our results suggested that the interaction of mitochondria and ER stress-enhanced HMGA2 played an important role in Cr (VI)-induced metabolic reprogramming from OXPHOS to glycolysis by binding directly to D-loop region of mtDNA. This work informs on the potential mode of action for Cr (VI)-induced tumors and builds on growing evidence regarding the contribution of cellular metabolic disruption contributing to carcinogenicity.

Curcumin attenuates Cr (VI)-induced cell growth and migration by targeting autophagy-dependent reprogrammed metabolism.

Hexavalent chromium [Cr (VI)] is a well-established carcinogen. Cr (VI)-treated cells are phenotypically characterized by aberrant levels of growth and migration. Curcumin, a polyphenolic compound from the plant turmeric, has been found to possess antiproliferation, anti-inflammation, and antioxidant properties. In this study, the effect of curcumin on Cr (VI)-induced cell survival and migration and the underlying mechanism were investigated. Cell viability assay on A549 and human embryonic lung fibroblast cells showed that curcumin at the concentration of 10 µM could significantly attenuate Cr (VI)-induced viability in both cell lines. Following Western blot assay and metabolomics assays, cotreatment with curcumin and Cr (VI) resulted in the suppression of Cr (VI)-induced glycolysis-, autophagy-, and migration-related proteins. Meanwhile, curcumin increased Cr (VI)-reduced oxidative phosphorylation (OXPHOS)-related proteins, COXIV and ND1. Moreover, curcumin suppressed Cr (VI)-induced mitochondrial dysfunction, mitochondrial mass decrease, and mitochondrial membrane potential loss. Treatment with curcumin for 24 h significantly attenuated pcATG4B-induced autophagy and the subsequent expression of glucose transporter 1, hexokinase II, and pyruvate kinase M2. Wound healing and transwell assay demonstrated that curcumin reduced Cr (VI)-induced cell migration. Taken together, these results showed that curcumin was able to attenuate Cr (VI)-induced cell viability and migration by targeting autophagy-dependent reprogrammed metabolism from OXPHOS to glycolysis.