Superfund Research Program
Arsenic-Induced Pseudohypoxia Drives Malignant Transformation in Lung Cancer
Project Leader: Walter T. Klimecki
Grant Number: P42ES004940
Funding Period: 2010-2017
Final Progress Reports
Year: 2016 2014
Leads that Klimecki and his research team developed last year suggested that arsenic induced aerobic glycolysis in lymphoblastoid cell lines. Within the Aims of this project, which is focused on determinants of individual variability in susceptibility to arsenic cytotoxicity, this finding was of great interest in part because of recently published findings which suggest that the induction of glycolysis was associated with resistance to chemical toxicity. The researchers built on those early observations using a lung epithelial cell line, a known human tissue target of arsenic, in studies of the BEAS-2B cell line. This non-malignant human cell line induced aerobic glycolysis in response to arsenic exposure, and provided an excellent model in which to explore susceptibility to arsenic toxicity. Their work in the prior funding period established two major findings in this model. First, researchers developed isogenic variants of this cell line that have dramatically different susceptibility to arsenite-induced cytotoxicity, by culturing BEAS-2B under different conditions (with and without serum). These derivative, isogenic cell lines, differing in arsenite IC50 by four-fold, have dramatically different gene expression patterns that will enable the team's continued search for genes that determine susceptibility to arsenite cytotoxicity. This model will also allow researchers to surmount a major obstacle that they encountered in the use of human lymphoid cells and lymphoblastoid cell lines, namely that they are refractory to gene transfer through infection or transfection. It is important to also note that the more arsenite-sensitive of the derived cell lines do not undergo glycolysis induction in response to arsenite exposure, supporting the research team's hypothesis that the induction of glycolysis is related to resistance to arsenic-induced cytotoxicity. A second key finding, published in the last funding period, described the relevance of arsenic-induced glycolysis to the acquisition of malignancy in the BEAS-2B cell line. In this publication they showed that two concurrent events, the acquisition of malignancy and the accumulation of hypoxia-inducible factor -1 alpha (HIF1A) protein, occur following arsenic exposure. If these two responses are reduced by suppressing HIF1A gene expression, the acquisition of malignancy resulting from arsenite exposure is greatly reduced. Taken together their work has identified novel effects of arsenic in dysregulating cellular energy metabolism that impact cellular sensitivity to cytotoxicity as well as arsenic-induced carcinogenesis. This work led to an NIEHS-funded exploratory R03 grant focused on one specific mechanistic explanation of how arsenic-altered cellular energy metabolism might impact the acquisition of malignancy.