Lung cancer formation and progression are heavily influenced by environmental factors such as smoking and environmental/occupational exposure. Metal elements such as nickel promote lung cancers. Nickel ion mimics cellular hypoxic responses by elevating the cellular level of hypoxia-inducible factor 1 alpha (HIF-1a) through inhibition of prolyl hydroxylase thereby preventing HIF-1 degradation by proteosomes. Cellular hypoxic responses facilitate tumor progression by regulating gene expression that promotes angiogenesis and cellular adaptation to hypoxia. These processes have increasingly been regarded as prime therapeutic targets for cancer treatments. It is therefore important to understand the basic mechanism of the hypoxic response and angiogenesis in tumor cells, and to identify novel regulatory elements that can serve as therapeutic targets for cancer treatments. Recent studies have revealed a close ties among Polo-like kinase 3 (Plk3), HIF-1a, tumorigenesis, and tumor angiogenesis: Plk3 knockout mice developed highly vascularized tumors in multiple tissues, including the lung, at an advanced age. Plk3-/- mouse embryonic fibroblasts (MEFs) express higher levels of angiogenic factor VEGF. In addition, Plk3 null MEFs express elevated levels of HIF-1a under hypoxic conditions. Furthermore, our most recent studies unveiled a direct regulation of HIF1a by Plk3 through phosphorylation. Plk3 is thus a potential tumor suppressor that regulates cellular hypoxic and angiogenic responses. Based on these previous observations, we hypothesized that Plk3 has a significant role in tumor angiogenesis and nickel-induced carcinogenesis in the lung by inhibiting hypoxic and angiogenic responses of the lung cancer cells. We propose three Specific Aims to test our hypothesis:
Aim 1. Studying whether the Plk3 protein level and/or activity is regulated in lung cancer cells under hypoxia and nickel treatments.
Aim 2. Determining the role of Plk3 in production of pro-angiogenic factors by lung cancer cells under hypoxia and nickel treatments.
Aim 3. Investigating the role of Plk3 in lung cancer cell proliferation and survival under hypoxia and nickel treatments.
These Aims are designed to answer two basic questions: 1. Is Plk3 relevant to lung cancer progression? 2. How does Plk3 regulate lung cancer progression? The proposed study should serve as a foundation for further in-depth evaluation on the function of Plk3 in tumor biology and the potential of Plk3 as a therapeutic target for lung cancers. The study should also contribute to our understanding of the mechanisms underlying the environmental relevant metals such as nickel in lung cancers.
The proposed study intends to explore the role of Polo-like kinase 3 (Plk3) in lung cancer. Lung cancer is one of the most prevalent cancer types and the leading cause of cancer-related death in America. It is also one of the most environmentally susceptible cancer types. The proposed study will use biochemical and molecular/cellular biological approaches to investigate the function of Plk3 in lung cancer cell models. The result of this study should provide significant new insights into the biology of lung cancer, the mechanism of how environmental relevant nickel metal affects lung cancer, and the potential of Plk3 as therapeutic target.
