Huihui Wang

Bio: Huihui Wang is an academic researcher from China Medical University (PRC). The author has contributed to research in topics: Oxidative stress & Arsenic. The author has an hindex of 20, co-authored 52 publications receiving 1272 citations. Previous affiliations of Huihui Wang include University of Arizona.

Arsenic Inhibits Autophagic Flux, Activating the Nrf2-Keap1 Pathway in a p62-Dependent Manner

Abstract: The Nrf2-Keap1 signaling pathway is a protective mechanism promoting cell survival. Activation of the Nrf2 pathway by natural compounds has been proven to be an effective strategy for chemoprevention. Interestingly, a cancer-promoting function of Nrf2 has recently been observed in many types of tumors due to deregulation of the Nrf2-Keap1 axis, which leads to constitutive activation of Nrf2. Here, we report a novel mechanism of Nrf2 activation by arsenic that is distinct from that of chemopreventive compounds. Arsenic deregulates the autophagic pathway through blockage of autophagic flux, resulting in accumulation of autophagosomes and sequestration of p62, Keap1, and LC3. Thus, arsenic activates Nrf2 through a noncanonical mechanism (p62 dependent), leading to a chronic, sustained activation of Nrf2. In contrast, activation of Nrf2 by sulforaphane (SF) and tert-butylhydroquinone (tBHQ) depends upon Keap1-C151 and not p62 (the canonical mechanism). More importantly, SF and tBHQ do not have any effect on autophagy. In fact, SF and tBHQ alleviate arsenic-mediated deregulation of autophagy. Collectively, these findings provide evidence that arsenic causes prolonged activation of Nrf2 through autophagy dysfunction, possibly providing a scenario similar to that of constitutive activation of Nrf2 found in certain human cancers. This may represent a previously unrecognized mechanism underlying arsenic toxicity and carcinogenicity in humans.

The Role of Reactive Oxygen Species in Arsenic Toxicity.

Abstract: Arsenic poisoning is a global health problem. Chronic exposure to arsenic has been associated with the development of a wide range of diseases and health problems in humans. Arsenic exposure induces the generation of intracellular reactive oxygen species (ROS), which mediate multiple changes to cell behavior by altering signaling pathways and epigenetic modifications, or cause direct oxidative damage to molecules. Antioxidants with the potential to reduce ROS levels have been shown to ameliorate arsenic-induced lesions. However, emerging evidence suggests that constructive activation of antioxidative pathways and decreased ROS levels contribute to chronic arsenic toxicity in some cases. This review details the pathways involved in arsenic-induced redox imbalance, as well as current studies on prophylaxis and treatment strategies using antioxidants.

Does Nrf2 contribute to p53-mediated control of cell survival and death?

Abstract: In response to oxidative stress, the transcription factor Nrf2 is upregulated and controls activation of many genes that work in concert to defend cells from damages and to maintain cellular redox homeostasis. p53 has been regarded as the guardian of the genome through its pro-oxidant and antioxidant functions. Under low levels of reactive oxygen species (ROS), "normal" amounts of p53 upregulates expression of antioxidant genes, protecting macromolecules from ROS-induced damage. However, at high levels or extended exposure of ROS, p53 expression is enhanced, activating pro-oxidant genes and resulting in p53-dependent apoptosis. We observed a two-phase Nrf2 expression controlled by p53. (i) The induction phase: when p53 expression is relatively low, p53 enhances the protein level of Nrf2 and its target genes to promote cell survival in a p21-dependent manner. (ii) The repression phase: when p53 expression is high, the Nrf2-mediated survival response is inhibited by p53. Our observation leads to the hypothesis that the p53-mediated biphasic regulation of Nrf2 may be key for the tumor-suppressor function of p53 by coordinating cell survival and death pathways.

Fluoride and arsenic exposure impairs learning and memory and decreases mGluR5 expression in the hippocampus and cortex in rats.

Abstract: Fluoride and arsenic are two common inorganic contaminants in drinking water that are associated with impairment in child development and retarded intelligence. The present study was conducted to explore the effects on spatial learning, memory, glutamate levels, and group I metabotropic glutamate receptors (mGluRs) expression in the hippocampus and cortex after subchronic exposure to fluoride, arsenic, and a fluoride and arsenic combination in rats. Weaned male Sprague-Dawley rats were assigned to four groups. The control rats drank tap water. Rats in the three exposure groups drank water with sodium fluoride (120 mg/L), sodium arsenite (70 mg/L), and a sodium fluoride (120 mg/L) and sodium arsenite (70 mg/L) combination for 3 months. Spatial learning and memory was measured in Morris water maze. mGluR1 and mGluR5 mRNA and protein expression in the hippocampus and cortex was detected using RT-PCR and Western blot, respectively. Compared with controls, learning and memory ability declined in rats that were exposed to fluoride and arsenic both alone and combined. Combined fluoride and arsenic exposure did not have a more pronounced effect on spatial learning and memory compared with arsenic and fluoride exposure alone. Compared with controls, glutamate levels decreased in the hippocampus and cortex of rats exposed to fluoride and combined fluoride and arsenic, and in cortex of arsenic-exposed rats. mGluR5 mRNA and protein expressions in the hippocampus and mGluR5 protein expression in the cortex decreased in rats exposed to arsenic alone. Interestingly, compared with fluoride and arsenic exposure alone, fluoride and arsenic combination decreased mGluR5 mRNA expression in the cortex and protein expression in the hippocampus, suggesting a synergistic effect of fluoride and arsenic. These data indicate that fluoride and arsenic, either alone or combined, can decrease learning and memory ability in rats. The mechanism may be associated with changes of glutamate level and mGluR5 expression in cortex and hippocampus.

The emerging role of the Nrf2–Keap1 signaling pathway in cancer

Abstract: The Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2 [Nrf2])-Keap1 (Kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1) signaling pathway is one of the most important cell defense and survival pathways. Nrf2 can protect cells and tissues from a variety of toxicants and carcinogens by increasing the expression of a number of cytoprotective genes. As a result, several Nrf2 activators are currently being tested as chemopreventive compounds in clinical trials. Just as Nrf2 protects normal cells, studies have shown that Nrf2 may also protect cancer cells from chemotherapeutic agents and facilitate cancer progression. Nrf2 is aberrantly accumulated in many types of cancer, and its expression is associated with a poor prognosis in patients. In addition, Nrf2 expression is induced during the course of drug resistance. Collectively, these studies suggest that Nrf2 contributes to both intrinsic and acquired chemoresistance. This discovery has opened up a broad spectrum of research geared toward a better understanding of the role of Nrf2 in cancer. This review provides an overview of (1) the Nrf2-Keap1 signaling pathway, (2) the dual role of Nrf2 in cancer, (3) the molecular basis of Nrf2 activation in cancer cells, and (4) the challenges in the development of Nrf2-based drugs for chemoprevention and chemotherapy.

Recent insights into the function of autophagy in cancer

Abstract: Macroautophagy (referred to here as autophagy) is induced by starvation to capture and degrade intracellular proteins and organelles in lysosomes, which recycles intracellular components to sustain metabolism and survival. Autophagy also plays a major homeostatic role in controlling protein and organelle quality and quantity. Dysfunctional autophagy contributes to many diseases. In cancer, autophagy can be neutral, tumor-suppressive, or tumor-promoting in different contexts. Large-scale genomic analysis of human cancers indicates that the loss or mutation of core autophagy genes is uncommon, whereas oncogenic events that activate autophagy and lysosomal biogenesis have been identified. Autophagic flux, however, is difficult to measure in human tumor samples, making functional assessment of autophagy problematic in a clinical setting. Autophagy impacts cellular metabolism, the proteome, and organelle numbers and quality, which alter cell functions in diverse ways. Moreover, autophagy influences the interaction between the tumor and the host by promoting stress adaptation and suppressing activation of innate and adaptive immune responses. Additionally, autophagy can promote a cross-talk between the tumor and the stroma, which can support tumor growth, particularly in a nutrient-limited microenvironment. Thus, the role of autophagy in cancer is determined by nutrient availability, microenvironment stress, and the presence of an immune system. Here we discuss recent developments in the role of autophagy in cancer, in particular how autophagy can promote cancer through suppressing p53 and preventing energy crisis, cell death, senescence, and an anti-tumor immune response.