Constitutive Activation of Epidermal Growth Factor Receptor Promotes Tumorigenesis of Cr(VI)-transformed Cells through Decreased Reactive Oxygen Species and Apoptosis Resistance Development

Abstract

Background: Chronic exposure to Cr(VI) causes cell transformation. Results: Cr(VI)-transformed cells exhibit activated EGFR, reduced ROS generation, and development of apoptosis resistance. Conclusion: Constitutive activation of EGFR promotes tumorigenesis of Cr(VI)-transformed cells.Significance: The findings provide a new understanding on carcinogenic mechanisms of not only Cr(VI) but also other metals, such as arsenic and nickel. It also can be used to formulate cancer prevention strategies.

Activation of Epidermal Growth Factor Receptor/p38/Hypoxia-inducible Factor-1α Is Pivotal for Angiogenesis and Tumorigenesis of Malignantly Transformed Cells Induced by Hexavalent Chromium

“…Ligand-induced EGFR dimerization triggers downstream signaling cascades including MAPK, PI3K-AKT, STAT, and PKC pathways. Our previous study has shown that constitutive activation of EGFR in Cr(VI)-transformed BEAS-2B cells is dependent on its ligand amphiregulin (12). Knockdown of EGFR reduced both tumor incidence and volume of Cr(VI)-transformed cells (12).…”

“…Changes from normal cells to malignantly transformed cells are considered the first stage of metal-induced carcinogenesis (12,13). The development of malignantly transformed cells into tumor is the second stage.…”

“…Those transformed cells are tumorigenic (12). Angiogenesis is a vital pathological process during tumorigenesis.…”

“…Our previous study has observed that EGFR was constitutively activated in Cr(VI)-transformed human bronchial epithelial BEAS-2B cells (12). Inhibition of EGFR by its shRNA or kinase inhibitor reduced tumorigenesis of Cr(VI)-transformed cells, indicating the essential role of EGFR in Cr(VI)-induced tumorigenesis (12). It has been reported that activated EGFR phosphorylated p38 MAPK (13).…”

“…Previous studies have demonstrated that signaling through tyrosine kinase EGF receptor (EGFR) regulates pro-angiogenic factors in tumor cells of different histological origin (9 -11). Our previous study has observed that EGFR was constitutively activated in Cr(VI)-transformed human bronchial epithelial BEAS-2B cells (12). Inhibition of EGFR by its shRNA or kinase inhibitor reduced tumorigenesis of Cr(VI)-transformed cells, indicating the essential role of EGFR in Cr(VI)-induced tumorigenesis (12).…”