Signaling and Targeting of Glutamate Dehydrogenase 1 in Metastatic Non-Small Cell Lung Carcinoma
Abstract
Lung cancer is the leading cause of cancer-related death in the US and worldwide. About 85% of lung cancers are non-small cell lung carcinoma (NSCLC) and 30% of NSCLC patients lack of a tumor-suppressing factor called LKB1. The 5-year survival rate for metastatic NSCLC is only around 3%, and clinically effective treatment of NSCLC remains difficult due to metastasis. Although there have been major breakthroughs that were resulted from the increased understanding about how lung cancers initiate and progress to metastasis that is the more deadly situation, the development of targeted agents in lung cancer is still in its infancy. This is in part due to lack of promising targets that are known to be specifically responsible for tumor initiation and metastasis in lung cancer. Thus, it is critical for cancer researchers to find new, promising therapeutic targets and develop strategy to block such targets in order to improve the clinical treatment and outcome of lung cancer patients. Recently cancer is indicated as a metabolic disease. Accumulating evidence suggests that cancer cells handle their metabolism quite differently from normal cells by consuming not only more glucose but also glutamine to generate more energy and building blocks. Therefore, such unique metabolic properties of cancer cells make cancer metabolism an attractive target in treatment of human cancers. ?Turning off? glutamine or glucose metabolism may only kill cancer cells or slow down their growth but leave normal cells alone. However, up to date, how changes of metabolism in cancer cells contribute to cancer cell growth and tumor metastasis is still unclear. We observed that one of the major enzymes in glutamine metabolism called glutamate dehydrogenase 1 (GDH1) exists more in cancer cells compared to normal cells. We found that GDH1 accelerates cancer cell growth by turning on an antioxidant enzyme called GPx1. Moreover, we recently found that GDH1 not only promotes cancer cell growth, but also speeds up metastasis by making cells survive through when they detach from the primary site. Interestingly, different from the way GDH1 controls cancer cell growth, GDH1 accelerates metastasis by turning on a protein factor called CamKK2, which activates a factor called ?AMPK.? CamKK2 is responsible for AMPK activation, when another AMPK activator LKB1 does not exist in cells. Our study suggests that GDH1 could be a potent anti-cancer target by inhibiting both cancer cell growth and tumor metastasis. Our findings also suggest that inhibiting GDH1 could block metastasis in lung cancer patients who lack LKB1, in which activation of AMPK will mainly rely on CamKK2. We thus developed small molecule drug called R162 that can specifically ?turn off? GDH1 in lung cancer cells. R162 specifically slowed down cancer cell growth, but had no or minimal effect on non-cancer cells. Thus, in this proposal, we will first test whether and how GDH1 manages CamKK2 and AMPK proteins in lung cancer cells of NSCLC to cause metastasis by comparing normal cells with cancer cells that have or do not have active GDH1. We will also test whether this specifically occurs in cancer cells that lack LKB1, where CamKK2 plays an important role in activating AMPK. We will also test whether inhibition of GDH1 by treating R162 can stop or at least slow down the cancer cell growth and tumor metastasis of laboratory cultured lung cancer cells and tumors derived from lung cancer patients. Lastly, we will develop the next generation of GDH1 inhibitor R162 with improved therapeutic effect, and the new drug design will be based on study of how our drug binds to the target protein GDH1 and turns it off. Such useful information will guide us to modify our current drug to generate more potent GDH1 inhibitors. Our studies will help to develop new therapeutic strategy to treat lung cancer patients. The GDH1 small molecule inhibitors developed by us are promising anti-cancer reagents
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710186
Entities
People
- Sumin Kang
Organizations
- Emory University
- United States Army