Molecular interplay between NOX1 and autophagy in cadmium-induced prostate carcinogenesis. Academic Article uri icon


  • Chronic exposure to cadmium (Cd), a class I carcinogen, leads to malignant transformation of normal prostate epithelial cells (RWPE-1). The constant generation of Cd-induced ROS and resulting ER stress induces cellular responses that are needed for cell survival, and autophagy has an important role in this process. However, the mechanisms that regulate Cd-induced ROS and how these differ in terms of acute and chronic cadmium exposure remain unexplained. Here, we show that acute or chronic Cd exposure facilitates NOX1 assembly by activating its cytosolic regulators p47phox and p67phox in RWPE-1cells. Upregulation of NOX1 complex proteins and generation of ROS activates unfolded protein response (UPR) via phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2 alpha (eIF2), and selective translation of activating transcription factor 4 (ATF4). Chronic Cd exposure constantly activates NOX1 complex and generates consistent ROS and ER stress that led to defective autophagy, wherein ATG5 expression is downregulated in contrast to acute Cd exposure. As a result, selective/defective autophagy creates depletion of autophagosome-lysosome fusion that gives a survival advantage to transforming cells, which is not available to RWPE-1cells acutely exposed to Cd. Knockdown of key molecules in a lockstep manner directly affects the most downstream autophagy pathways in transforming cells. Overall, this study demonstrates that assembly of NOX1 complex proteins is indispensable for Cd-induced persistent ROS and controls ER stress-induced defective autophagy in mice and humans.

published proceedings

  • Free Radic Biol Med

altmetric score

  • 1.75

author list (cited authors)

  • Tyagi, A., Chandrasekaran, B., Navin, A. K., Shukla, V., Baby, B. V., Ankem, M. K., & Damodaran, C.

citation count

  • 1

complete list of authors

  • Tyagi, Ashish||Chandrasekaran, Balaji||Navin, Ajit K||Shukla, Vaibhav||Baby, Becaa V||Ankem, Murali K||Damodaran, Chendil

publication date

  • April 2023