The fate of cell survival or death is a tightly regulated. Apoptosis, one of the major cell death mechanisms, is defective in many cancers. Apoptosis occurs in small fraction of cells within the irradiated solid tumors. Autophagy, a highly conserved self-elimination mechanism that utilizes lysosome/vacuoles for cellular degradation is a backup cell death pathway when apoptosis is blocked. Our preliminary data support the hypothesis that autophagy is an important alternative cell death mechanism in tumor cells exposed to ionizing radiation when the apoptotic pathway is blocked. In the absence of pro-apoptotic proteins, Bak/Bax or caspase 3/7, we found that autophagy is upregulated and occurred in over 50% of irradiated cells. As a consequence, we found that up-regulation autophagy confers increased radiation sensitivity of cancer cells. Central to this hypothesis is the concept that Bak/Bax or caspase 3/7 negatively regulate autophagy, upon radiation-induced stress and that autophagy is enhanced in cells lacking these pro-apoptotic proteins. We believe that induction of autophagy through 1) direct activation of autophagic signaling by mTOR inhibitors or overexpression of autophagic proteins;or 2) inhibition of Bak/Bax or caspase 3/7, will enhance the biological effects of radiation in cancer models.
Three specific aims are proposed to test this hypothesis.
Specific Aim 1 will identify mechanisms by which Bak/Bax or caspase 3/7 regulate radiation-induced autophagy.
Specific Aim 2 will determine whether inhibition of Bak/Bax or caspase 3/7, induction of the autophagic pathway, and enhanced radiosensitization is a global response in cancer cells.
Specific Aim 3 will determine whether induction of autophagic signaling by inhibition of mTOR or over expression of autophagic proteins enhances radiation response. The proposed study is to understand the molecular interaction between apoptosis and autophagy during radiation-induced stress and to identify novel targets for enhancing radiotherapy in cancer models. The significance of this study is to expand our understanding of the complex molecular signaling, which determines the fate of irradiated cells. This knowledge will be explored to improve the efficacy of conventional radiotherapy that is being used for cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA125842-03
Application #
7623045
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Salnikow, Konstantin
Project Start
2007-07-01
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
3
Fiscal Year
2009
Total Cost
$233,320
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Li, Bo; Blanc, Justin M Le; Sun, Yunguang et al. (2014) Assessment of M867, a selective caspase-3 inhibitor, in an orthotopic mouse model for non-small cell lung carcinoma. Am J Cancer Res 4:161-71
Giacalone, Nicholas J; Den, Robert B; Eisenberg, Rosana et al. (2013) ALDH7A1 expression is associated with recurrence in patients with surgically resected non-small-cell lung carcinoma. Future Oncol 9:737-45
Sun, Yunguang; Nowak, Kamila A; Zaorsky, Nicholas G et al. (2013) ALK inhibitor PF02341066 (crizotinib) increases sensitivity to radiation in non-small cell lung cancer expressing EML4-ALK. Mol Cancer Ther 12:696-704
Uzhachenko, Roman; Issaeva, Natalia; Boyd, Kelli et al. (2012) Tumour suppressor Fus1 provides a molecular link between inflammatory response and mitochondrial homeostasis. J Pathol 227:456-69
Sun, Yunguang; Zheng, Siyuan; Torossian, Artour et al. (2012) Role of insulin-like growth factor-1 signaling pathway in cisplatin-resistant lung cancer cells. Int J Radiat Oncol Biol Phys 82:e563-72
Ausborn, Natalie L; Le, Quynh Thu; Bradley, Jeffrey D et al. (2012) Molecular profiling to optimize treatment in non-small cell lung cancer: a review of potential molecular targets for radiation therapy by the translational research program of the radiation therapy oncology group. Int J Radiat Oncol Biol Phys 83:e453-64
Li, Bo; Torossian, Artour; Sun, Yunguang et al. (2012) Higher levels of c-Met expression and phosphorylation identify cell lines with increased sensitivity to AMG-458, a novel selective c-Met inhibitor with radiosensitizing effects. Int J Radiat Oncol Biol Phys 84:e525-31
Sun, Yunguang; Giacalone, Nicholas J; Lu, Bo (2011) Terameprocol (tetra-O-methyl nordihydroguaiaretic acid), an inhibitor of Sp1-mediated survivin transcription, induces radiosensitization in non-small cell lung carcinoma. J Thorac Oncol 6:8-14
Sun, Yunguang; Moretti, Luigi; Giacalone, Nicholas J et al. (2011) Inhibition of JAK2 signaling by TG101209 enhances radiotherapy in lung cancer models. J Thorac Oncol 6:699-706
Li, Bo; Torossian, Artour; Li, Wenyan et al. (2011) A novel bioluminescence orthotopic mouse model for advanced lung cancer. Radiat Res 176:486-93

Showing the most recent 10 out of 19 publications