Arsenic-Induced Pseudohypoxia Drives Malignant Transformation in Lung Cancer

Problem: 

Although it is well known that exposure to arsenic can lead to cancer and a number of other diseases, the exact mechanism through which this occurs remains unclear. Studies have shown that arsenic can also disrupt metabolism, a process that all cells in the body use to get energy. This process is also known to be disrupted in the development of cancer.

Dr. Walt Klimecki is investigating the intersection of arsenic, cellular metabolism, and cancer. Using both cell culture and mouse models, he will define the steps that occur during arsenic-induced disruption of metabolism. Preliminary studies have shown that cells exposed to arsenic show a psuedo-hypoxic response, shifting their metabolism to processes typically seen in oxygen deprivation, although oxygen remains present. He expects that his studies will link these arsenic-induced metabolic changes to the metabolic changes seen in cancer.

Significance: 

Understanding the mechanism(s) by which arsenic causes cancer will open the door to new potential modes of intervention (e.g. metabolism-modifying drugs such as metformin), and could shed light on a broad range of arsenic-associated chronic diseases beyond cancer.

Specific Aims: 
  1. Define the occurrence of metabolic disruption, loss of epithelial identity, and malignant transformation in a non-malignant pulmonary epithelial cell line, BEAS-2B; and
  2. Define key components of the arsenite-induced "pseudo-hypoxic" response and their contribution to early events leading to malignant transformation.