Krebs Cycle Signaling for Therapy of Metastatic Lung Cancer
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). The five-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 deadlier 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, which should be based on full understanding of the cellular events how signaling network orchestrates the metastasis process. 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. It is noted that metabolic features of cancer cells differ from normal cells by consuming more glucose and glutamine to generate more energy and cellular components. However, accumulating evidence suggests that metastasizing cancer cells handle their metabolism quite different from cancer cells at their primary site. While fast proliferating primary cancer cells tend to generate energy and building blocks through a non-mitochondrial pathway called “aerobic glycolysis,” elevation of mitochondria biosynthesis-related genes is observed in disseminated circulating tumor cells. Understanding how the unique mitochondria metabolic property turns on the metastatic switch and identifying the key factors in this pathway will provide potent targets for the treatment of metastatic cancer. “Turning off” such mitochondrial target will specifically kill metastatic cancer cells or slow down their survival potential during circulation. However, to date, how changes of metabolism in mitochondria of cancer cells contribute to metastasis is still unclear. Non-metastatic cancer cells die when detached from original site, but metastatic cancer cells survive through this detachment-induced cell death (a.k.a. anoikis). To find out the novel mitochondria factor that is essential for tumor cell survival during dissemination, we individually removed 120 mitochondria metabolic factors and monitored which gene loss would kill cancer cells when cells are detached. Among 120 candidates, we found ATP-specific succinyl-CoA synthetase beta (SUCLA2, a.k.a. A-SCS) as the most potent target that could be responsible for metastasis. To glean at the mechanism how SUCLA2 contributes to metastasis, global changes in metabolites and gene levels were monitored in lung cancer cells missing SUCLA2. Metabolites related to redox balance were altered in SUCLA2 missing lung cancer cells. Whole gene level assessment result showed that genes called p53-responsive gene 3 (PRG3) and PALM2-AKAP2 fusion (AKAP2), which are implicated in redox management, were dramatically decreased by the result of SUCLA2 loss. These results suggest that mitochondrial SUCLA2 in the Krebs cycle may be an essential metastasis promoting factor in lung cancer. SUCLA2 may do this by providing survival advantage through removing elevated reactive oxygen species (ROS) produced by managing AKAP2 and PRG3 upon dissemination. Thus, in this proposal, we will first test whether SUCLA2 is an essential factor to cause metastasis by comparing normal cells with cancer cells that have or do not have active SUCLA2 using NSCLC as a research platform. We will examine whether this specifically occurs in disseminated cancer cells that have abrupted redox balance and whether SUCLA2 plays an important role in protecting cancer cells from ROS-mediated cell death. We will also uncover whether SUCLA2 plays an essential role in promoti
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110213
Entities
People
- Sumin Kang
Organizations
- Emory University
- United States Army