Protein kinase A activation by beta-Lapachone is associated with apoptotic cell death in NQO1-overexpressing breast cancer cellsopen access
- Zada, Sahib; Hwang, Jin Seok; Ahmed, Mahmoud; Trang Huyen Lai; Trang Minh Pham; Kim, Dong-Hee; Kim, Deok Ryong
- Issue Date
- SPANDIDOS PUBL LTD
- apoptosis; PKA; beta-lapachone; ROS; NQO1; breast cancer cells
- ONCOLOGY REPORTS, v.42, no.4, pp.1621 - 1630
- Journal Title
- ONCOLOGY REPORTS
- Start Page
- End Page
- One million females are diagnosed worldwide every year with breast cancer, and the mortality rate of these patients remains high. Several treatments, including surgery, are available for breast cancer. beta-Lapachone (beta-Lap), a natural quinone compound, has been developed for cancer treatment due to its strong cytotoxic effect through its action on NAD(P)H:quinone oxidoreductase 1 (NQO1)-dependent activity. However, the mechanism in regards to how beta-Lap induces cytotoxicity in breast cancer cells is still elusive. In the present study, we showed that beta-Lap induced apoptotic cell death via activation of protein kinase A (PKA) in NQO1-overexpressing MDA-MB-231 human breast cancer cells. This PKA-dependent cell death was observed solely in NQO1-overexpressing 231 cells via the high production of reactive oxygen species (ROS). Cell survival of antioxidant [N-acetylcysteine (NAC)]-treated NQO1-overexpressing 231 cells was significantly recovered, and NQO1-negative 231 cells did not respond to beta-Lap. Antiapoptotic proteins such as Bcl2 and Bcl-xL were decreased, while proapoptotic proteins, including cytochrome c, activation of caspase-3, and cleavage of PARP were increased after beta-Lap treatment of NQO1-overexpressing 231 cells. Furthermore, PKA activators, forskolin or dibutyryl-cAMP, an analog of cAMP, aggravated the beta-Lap-induced apoptotic cell death by decreasing antiapoptotic proteins and further activating proapoptotic proteins in NQO1-positive 231 cells. Treatment with a PKA inhibiter, H89, significantly increased cell viability even in NQO1-overexpressing cells treated with beta-Lap. These data showed that beta-Lap activated PKA via ROS accumulation, subsequently leading to apoptotic cell death in NQO1-positive breast cancer cells.
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- College of Medicine > Department of Medicine > Journal Articles
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