Reactive oxygen species mediate Cr(VI)-induced carcinogenesis through PI3K/AKT-dependent activation of GSK-3β/β-catenin signaling

Abstract

Cr(VI) compounds are known human carcinogens that primarily target the lungs. Cr(VI) produces reactive oxygen species (ROS), but the exact effects of ROS on the signaling molecules involved in Cr(VI)-induced carcinogenesis have not been extensively studied. Chronic exposure of human bronchial epithelial cells to Cr(VI) at nanomolar concentrations (10 - 100 nM) for 3 months not only induced cell transformation, but also increased the potential of these cells to invade and migrate. Injection of Cr(VI)-stimulated cells into nude mice resulted in the formation of tumors. Chronic exposure to Cr(VI) increased levels of intracellular ROS and antiapoptotic proteins. Transfection with catalase or superoxide dismutase (SOD) prevented Cr(VI)-mediated increases in colony formation, cell invasion, migration, and xenograft tumors. While chronic Cr(VI) exposure led to activation of signaling cascades involving PI3K/AKT/GSK-3β/β-catenin and PI3K/AKT/mTOR, transfection with catalase or SOD markedly inhibited Cr(VI)-mediated activation of these signaling proteins. Inhibitors specific for AKT or β-catenin almost completely suppressed the Cr(VI)-mediated increase in total and active β-catenin proteins and colony formation. In particular, Cr(VI) suppressed autophagy of epithelial cells under nutrition deprivation. Furthermore, there was a marked induction of AKT, GSK-3β, β-catenin, mTOR, and carcinogenic markers in tumor tissues formed in mice after injection with Cr(VI)-stimulated cells. Collectively, our findings suggest that ROS is a key mediator of Cr(VI)-induced carcinogenesis through the activation of PI3K/AKT-dependent GSK-3β/β-catenin signaling and the promotion of cell survival mechanisms via the inhibition of apoptosis and autophagy.

Curcumin Promotes Cell Cycle Arrest and Inhibits Survival of Human Renal Cancer Cells by Negative Modulation of the PI3K/AKT Signaling Pathway

“…Our results show that curcumin markedly inhibits proliferation of these cells, induces cell apoptosis in a dosedependent manner, potentially via modulation of expression of Bcl-2 and Bax, and initiates cell cycle arrest in G 2 /M phase. All of the above beneficial anticancer effects of curcumin may be related to negative regulation of the PI3K/ AKT signaling pathway, which plays an important role in tumor initiation and progression [21][22][23]. Our data are consistent with previous reports that demonstrated that curcumin inhibits phosphorylation of Foxo transcription factor by abolishing AKT phosphorylation [24].…”

“…The intracellular target of curcumin is not known. Previous reports demonstrated that curcumin blocks the PI3K/AKT pathway [21] which can be beneficial for anticancer treatments. To further explore this, in the current study we examined the effects of curcumin on RCC survival, apoptosis, as well as its effects on cell cycle and the PI3K/AKT pathway.…”

How the Location of Superoxide Generation Influences the β-Cell Response to Nitric Oxide

“…This finding suggests that superoxide and peroxynitrite activate GSK3 through pathways independent of the unfolded protein response. Consistent with this interpretation, superoxide (44,45) and peroxynitrite (46) have been shown to induce GSK3 phosphorylation through a PI3K/Akt-dependent pathway. MAPK are differentially activated by ROS and RNS.…”

Tobacco nitrosamine NNK increases ALDH-positive cells via ROS-Wnt signaling pathway in A549 human lung cancer cells

“…signaling by NNK PI3K-Akt pathway has been reported to be involved in the activation of β-catenin via ROS (Son et al, 2013). To examine the involvement of Akt to the NNK effects, we examined the phosphorylation of Akt.…”