Chronic exposure to inorganic arsenic is a worldwide public health problem that has been associated to increased risks of developing cancers of the lung, skin, and bladder. Among these malignancies, arsenic- induced lung cancer presents with the highest mortality rate. The precise carcinogenic mechanism of arsenic has not yet been fully elucidated despite many years of research and the severity of the health effects associated to its exposure. We have previously reported that environmentally relevant, low doses of arsenic block autophagy, which resulted in prolonged activation of Nrf2, the main orchestrator of the adaptive antioxidant and pro-survival response. Specifically, arsenic-induced Nrf2 activation does not occur through the canonical, reactive oxygen species (ROS)-sensing mechanism but through the autophagy-dependent, non- canonical mechanism. Autophagy is a bulk degradation pathway that degrades damaged organelles and protein aggregates. Autophagy blockage can result in accumulation of defective mitochondria and excessive ROS production, which cause DNA mutations. Nrf2 activation is well known for its cellular protection against ROS stress, which can enable arsenic-exposed cells to survive and sustain gene mutations that drive malignant transformation. Therefore, we hypothesize that prolonged activation of Nrf2 resulting from arsenic-induced autophagy blockage is essential for the arsenic-mediated malignant transformation. Our hypothesis is supported by several recent publications demonstrating that the tumorigenic effect of prolonged Nrf2 activation in autophagy-deficient mice was abolished by concurrent Nrf2 knockout. Moreover, earlier studies have found high constitutive levels of Nrf2 in many cancer cells, which favor their proliferation and chemo resistance, an effect known as the dark side of Nrf2. We have generated substantial amounts of data indicating that arsenic blocks autophagy by inhibiting the autophagosome-lysosome fusion step. Three SNAREs mediate the fusion: Stx17 on the outer membrane of the autophagosome interacts through SNAP29 with VAMP8 that resides on the lysosome membrane. We believe that genetic ablation of any of these proteins should prevent the fusion of the autophagosome with the lysosome, and the effects of this ablation should mimic the effects of arsenic- mediated p62-dependent Nrf2 up regulation. To better understand arsenic carcinogenicity, we propose:
Aim 1 : Elucidate the detailed molecular mechanism by which arsenic blocks autophagosome- lysosome fusion.
Aim 2 : Determine if autophagy dysregulation and prolonged Nrf2 activation are essential for malignant transformation.
Aim 3 : Test the tumorigenicity of cell lines and correlate it with prolonged Nrf2 activation. Impact: A detailed and thorough understanding of the molecular events leading to the prolonged Nrf2 activation in arsenic-induced carcinogenesis will prove extremely valuable in the generation of preventive and therapeutic strategies, as well as in the identification of biomarkers, for the populations at risk.

Public Health Relevance

Arsenic is a contaminant of drinking water and food that causes many diseases such as cancer, of which lung cancer is the deadliest. The project we propose aims to investigate the detailed mechanism by which arsenic causes lung cancer. In turn, this will allow us to identify markers of exposure to identify populations at risk of developng arsenic-induced lung cancer as well as to develop tailored therapies for the individuals who have already developed arsenic-induced lung cancer.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Systemic Injury by Environmental Exposure (SIEE)
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Reinlib, Leslie J
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University of Arizona
Schools of Pharmacy
United States
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Rojo de la Vega, Montserrat; Chapman, Eli; Zhang, Donna D (2018) NRF2 and the Hallmarks of Cancer. Cancer Cell 34:21-43
Tao, Shasha; Rojo de la Vega, Montserrat; Chapman, Eli et al. (2018) The effects of NRF2 modulation on the initiation and progression of chemically and genetically induced lung cancer. Mol Carcinog 57:182-192
Rojo de la Vega, Montserrat; Zhang, Donna D (2018) NRF2 Induction for NASH Treatment: A New Hope Rises. Cell Mol Gastroenterol Hepatol 5:422-423
Liu, Pengfei; Rojo de la Vega, Montserrat; Sammani, Saad et al. (2018) RPA1 binding to NRF2 switches ARE-dependent transcriptional activation to ARE-NRE-dependent repression. Proc Natl Acad Sci U S A 115:E10352-E10361
Tian, Wang; Rojo de la Vega, Montserrat; Schmidlin, Cody J et al. (2018) Kelch-like ECH-associated protein 1 (KEAP1) differentially regulates nuclear factor erythroid-2-related factors 1 and 2 (NRF1 and NRF2). J Biol Chem 293:2029-2040
Dodson, Matthew; de la Vega, Montserrat Rojo; Harder, Bryan et al. (2018) Low-level arsenic causes proteotoxic stress and not oxidative stress. Toxicol Appl Pharmacol 341:106-113
Rojo de la Vega, Montserrat; Zhang, Donna D; Wondrak, Georg T (2018) Topical Bixin Confers NRF2-Dependent Protection Against Photodamage and Hair Graying in Mouse Skin. Front Pharmacol 9:287