Superfund Research Program
Arsenic-Induced Pseudohypoxia Drives Malignant Transformation in Lung Cancer
Project Leader: Walter T. Klimecki
Grant Number: P42ES004940
Funding Period: 2010-2017
Project Summary (2015-2017)
Arsenic is one of the most common metals found as a contaminant at Superfund sites, particularly those involving legacy mining operations. Arsenic may be the most striking example of an incontrovertible human carcinogen for which there is little scientific agreement as to mechanism of action. We have recently published a novel effect of inorganic arsenic in cultured human cells, the shift from oxidative energy metabolism to anaerobic glycolysis, in what has the appearance of an inappropriately launched hypoxia response. The scientific literature is witnessing exponential growth in reports linking fundamental energy metabolism to the development and progression of cancer. Combining this evidence together, project researchers believe that the disruption of energy metabolism, a process occurring in all cells of the body, could provide a rational explanation for the remarkable diversity of arsenic targets of carcinogenicity — the disruption of a fundamental process that manifests as a similar disease in multiple tissue contexts. Preliminary data from the research team demonstrates that genetically manipulating the hypoxia-mimetic effect of arsenite in an in vitro model of arsenite-induced lung cancer has a significant impact on arsenic carcinogenicity.
The overall objective of this research project is to accurately define the extent of the perturbation of cellular energy metabolism by arsenic, and to identify the important regulators of this process. The guiding hypothesis is that the carcinogenic mechanism of inorganic arsenic involves its hypoxia-mimetic response, and includes HIF-mediated pathway gene induction, as well as altered carbohydrate metabolism that favors the production of macromolecular precursors.
The researchers are structuring this effort through two aims:
- Define the occurrence of metabolic disruption, loss of epithelial identity, and malignant transformation in a non-malignant pulmonary epithelial cell line, BEAS-2B; and
- Define key components of the arsenite-induced "pseudo-hypoxic" response and their contribution to early events leading to malignant transformation.
Even though arsenic is one of the most proven cancer-causing agents to which people are environmentally exposed, how it causes cancer is still not known. This project is pursuing an exciting new possibility that arsenic could alter cell behavior through altering the way the cells of the body process sugar for energy. Knowing this could lead to new ways to prevent the diseases that arsenic causes, including cancer.