期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
卷 1840, 期 3, 页码 1014-1027出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbagen.2013.11.020
关键词
ATM/ATR; DNA strand break; Lung cancer cell; Malabaricone C; MAPK; Mitochondrial dysfunction
Background: Given that lung cancer is the second leading cause of cancer-related deaths with low survival rates, the project was aimed to formulate an efficient drug with minimum side effects, and rationalize its action mechanistically. Methods: Mitochondria deficient cells, shRNA-mediated BCL2 and ATM depleted cells and pharmacological inhibition of DNA-damage response proteins were employed to explore the signaling mechanism governed between nucleus and mitochondria in response to mal C. Results: Mal C decreased cell viability in three lung carcinoma cells, associated with DNA damage, p38-MAPK activation, imbalance in BAX/BCL2 expression, mitochondrial dysfunction and cytochrome-c release. Mitochondria depletion and p38-MAPK inhibition made A549 cells extremely resistant, but BCL2 knock-down partially sensitized the cells to mal C treatment. The mal C-induced apoptosis in A549 cells was initiated by DNA single strand breaks that led to double strand breaks (DSBs). DSB generation paralleled the induction of ATM- and ATR-mediated CHK1 phosphorylation. ATM silencing and ATR inhibition partially attenuated the mal C-induced p38-MAPK activation, CHK1 phosphoiylation and apoptosis, which were completely suppressed by CHK1 inhibition. Conclusions: Mal C activates the ATM-CHK1-p38 MAPK cascade to cause mitochondrial cell death in lung carcinoma cells. General significance: Given that mal C has appreciable natural abundance and is non-toxic to mice, further in vivo evaluation would help in establishing its anti-cancer property. (C) 2013 Elsevier B.V. All rights reserved.
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