The role of autophagy in metal-induced urogenital carcinogenesis

Abstract

Environmental and/or occupational exposure to metals such as Arsenic (As), Cadmium (Cd), and Chromium (Cr) have been shown to induce carcinogenesis in various organs, including the urogenital system. However, the mechanisms responsible for metal-induced carcinogenesis remain elusive. We and others have shown that metals are potent inducers of autophagy, which has been suggested to be an adaptive stress response to allow metal-exposed cells to survive in hostile environments. Albeit few, recent experimental studies have shown that As and Cd promote tumorigenesis via autophagy and that inhibition of autophagic signaling suppressed metal-induced carcinogenesis. In light of the newly emerging role of autophagic involvement in metal-induced carcinogenesis, the present review focuses explicitly on the mechanistic role of autophagy and potential signaling pathways involved in As-, Cd-, and Cr-induced urogenital carcinogenesis.

Keywords: Arsenic; Cadmium; Chromium; Impaired autophagy; Molecular signaling.

Figure 1:

Molecular pathways involved in the regulation of autophagy in metal-induced carcinogenesis. Metal induces uncontrolled oxidative stress and excessive ROS production, which triggers ER stress, activation of antioxidant response (p62/Nrf2), and DNA damage. Metal exposure also induces epigenetic changes that affect DNA repair pathways (ERCC1, XRCC), inflammation (NFκB), cell proliferation (Ras/MAPK/PI3K/mTORC1), and survival (Bcl-2). Cellular stress conditions like oxidative stress, hypoxia and ER stress activate autophagy to enable cells to adapt to unfavorable conditions.

Figure 2:

Induction of autophagy in metal-induced prostate carcinogenesis. Cd and As have been shown to mediate effects using the same molecular pathways. Both promote carcinogenesis by directly triggering proteins involved in cell proliferation (ERK/MAPK), and by increasing oxidative stress through epigenetic changes or disruption of antioxidant signaling. Increased ROS triggers ER stress and autophagic responses that lead to CaP. Cr also causes excessive ROS production and NFκB activation resulting in cell survival. Albeit limited, studies have shown that autophagy is a key event during the malignant transformation of metal-exposed prostate cells. Dotted lines represent plausible mechanisms involved.

Figure 3:

Metal-induced autophagy-mediated bladder carcinogenesis. As exposure induces GSH mediated superoxide formation that affects several pathways, including Nrf2-Keap1 and ATF4-mediated UPR. Inhibition of mTORC1 or activation of ULK1 and Atg induced autophagy resulting in the malignant transformation of bladder cells. Cd exposure increased Nrf2 binding to the ARE promoter in p62, causing an increase in antioxidants and concomitant ROS inhibition ultimately leading to carcinogenesis of bladder epithelial cells. Similarly, Cr-exposure dysregulated the p62 mediated Nrf2-Keap1 pathway and promoted constitutive activation of Nrf2.