PKC is an indispensable factor in promoting environmental toxin chromium-mediated transformation and drug resistance

Aging (Albany NY). 2022 Feb 24;14(4):1678-1690. doi: 10.18632/aging.203917. Epub 2022 Feb 24.

Abstract

Hexavalent chromium [Cr(VI)] pollution is a serious environmental problem, due to not only its toxicity but also carcinogenesis. Although studies reveal several features of Cr(VI)-induced carcinogenesis, the underlying mechanisms of how Cr(VI) orchestrates multiple mitogenic pathways to promote tumor initiation and progression remain not fully understood. Src/Ras and other growth-related pathways are shown to be key players in Cr(VI)-initiated tumor prone actions. The role of protein kinase C (PKC, an important signal transducer) in Cr(VI)-mediated carcinogenesis has not been thoroughly investigated. In this study, using human bronchial/lung epithelial cells and keratinocytes, we demonstrate that PKC activity is increased by transient or chronic Cr(VI) exposure, which plays no role in the activation of Src/Ras signaling and ROS upregulation by this metal toxin. PKC in chronic Cr(VI)-treated cells stabilizes Bcl-2 to mitigate doxorubicin (an anti-cancer drug)-mediated apoptosis. After the suppression of this kinase by GO6976 (a PKC inhibitor), the cells chronically exposed to Cr(VI) partially regain the sensitivity to doxorubicin. However, when co-suppressed PKC and Ras, the chronic Cr(VI)-treated cells become fully responsive to doxorubicin and are unable to be transformed. Taken together, our study provides a new insight into the mechanisms, in which PKC is an indispensable player and cooperates with other mitogenic pathways to achieve Cr(VI)-induced carcinogenesis as well as to establish drug resistance. The data also suggest that active PKC can serve as a potential biomarker for early detection of health damages by Cr(VI) and therapeutic target for developing new treatments for diseases caused by Cr(VI).

Keywords: Bcl-2; Cr(VI); PKC; Ras; Src; tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogenesis / metabolism
  • Cell Transformation, Neoplastic* / metabolism
  • Chromium* / toxicity
  • Doxorubicin / adverse effects
  • Drug Resistance
  • Humans

Substances

  • Chromium
  • Doxorubicin