Calcium metabolism and lung cancer preneoplasia

PROJECT SUMMARY/ABSTRACT Lung cancer is the second deadliest cancer. Despite its prevalence and unfavorable consequences, current therapeutic approaches are limited. The proposed study aims to understand the biology of lung tumorigenesis and use that knowledge to lay a foundation to develop potential treatment regimens for lung cancer. Normal cells undergo finite division and remain quiescent. The dimerization partner, RB-like, E2F, and multi-vulval class B (DREAM) complex is a cell cycle-regulatory multiprotein complex that orchestrates cell quiescence and the cell cycle. In association with RBL2/p130 (retinoblastoma-like protein 2), E2F4, and DP1 (E2F dimerization partner 1), the DREAM complex is localized to the promoters of cell cycle-regulating genes, repressing their transcription and inducing cell quiescence via G0 and G1 arrest. However, dysregulation of such a process causes the cell quiescence exit and re-entry into abnormal cell proliferation, likely leading to tumor initiation and progression. Nonetheless, the mechanism of how the DREAM complex is aberrantly regulated in cancer cells remains elusive. Comprehensive approaches employing genetically engineered animal models and unbiased screening suggest that PAF (PCNA-associated factor/KIAA0101/PCLAF) plays the oncogenic roles in non-small cell lung carcinoma (NSCLC) by remodeling the DREAM complex. Intriguingly, we found that aberrantly regulated calcium signaling enhances the DREAM complex-mediated gene transactivation. Despite the implication of Ca2+ signaling in cancer, the oncogenic roles of Ca2+ signaling in lung cancer were poorly understood. Based on the preliminary results, we hypothesize that dysregulated calcium signaling contributes to NSCLC tumorigenesis via the DREAM complex, which appears to be a targetable vulnerability of lung cancer. The hypothesis will be tested by pursuing two specific aims: Aim 1. To determine the therapeutic impact of NFAT inhibitors on lung tumorigenesis; Aim 2. To dissect the mechanism of NFAT-mediated lung tumorigenesis. Completing the proposed research is expected to advance the development of a new approach for treating lung cancer based on a novel targetable molecular mechanism involved in lung tumorigenesis.