Investigation of the Pro-Survival Signaling Mediated by Chromium(VI) in The Lung

PROJECT SUMMARY Hexavalent chromium [Cr(VI)] is a well-known environmental carcinogen. The exposure of Cr(VI), throughcontaminated soil, air particles and drinking water, is a major concern for the public health in the US andworldwide. While various means to protect the environment have dramatically reduced the onset of humandiseases (including lung cancer) caused by the exposures of Cr(VI), there are still no effective strategies to preventthe pollution and to block the process of tumor promotion. This is because of the lack of the knowledge about themolecular targets involved in Cr(VI)-mediated carcinogenesis. Thus, there is an ugent need for elucidating theunderlying mechanisms of Cr(VI)-mediated carcinogenic activities in cells. Studies have demonstrated that Cr(VI)exposure perturbs the state of redox, which then promotes uncontrollable cell growth and further tumorigenesis.However, the link between Cr(VI) exposure and tumorigenic tendency is not fully understood. Our preliminary dataprovided a novel observation that upon Cr(VI) treatment, the intracellular receptor src was activated in lungepithelial cells, which further triggered Ras signaling for the promotion of cell growth and transformation. We alsodemonstrated that the expression level of anti-apoptotic factor Bcl-2 was increased, which appeared throughincreasing its protein stability. Furthermore, the increase of Bcl-2 expression and activity was dependent upon Rasactivation in Cr(VI)-mediated lung carcinogenesis. Based on the information, the long-term goal of our researchis to elucidate the underlying mechanism of Cr(VI)-mediated tumorigenesis. We will use the obtained knowledgeto design new means or inhibitors to target potential signaling molecules (perhaps src, Ras or Bcl-2), and to furthervalidate their suppressive effects on Cr(VI)-induced transformation or carcinogenesis. Our immediate hypothesisof the proposal is that Cr(VI) exposure activates src/Ras signaling and further upregulates Bcl-2 forpromoting lung cancer genesis and development. In order to test the hypothesis, two specific aims are formed:1) to investigate the mechanisms by which Ras functions in Cr(VI)-induced transformation; and 2) to study howBcl-2 stability is affected by Cr(VI) treatment for the promotion of tumorigenesis. The outcomes of these studieswill provide valuable information to guide the development of new chemo-prevention methods and strategies ofenvironmental protection from Cr(VI) pollution.