Increasing cisplatin sensitivity by schedule-dependent inhibition of AKT and Chk1 |
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Authors: | Lei Duan Ricardo E Perez Michael Hansen Steven Gitelis Carl G Maki |
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Affiliation: | 1.Department of Anatomy and Cell Biology; Rush University Medical Center; Chicago, IL USA;2.Section of Orthopedic Oncology; Department of Orthopedic Surgery; Rush University Medical Center; Chicago, IL USA |
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Abstract: | The effectiveness of DNA damaging chemotherapy drugs can be limited by activation of survival signaling pathways and cell cycle checkpoints that allow DNA repair. Targeting survival pathways and inhibiting cell cycle checkpoints may increase chemotherapy-induced cancer cell killing. AKT and Chk1 are survival and cell cycle checkpoint kinases, respectively, that can be activated by DNA damage. Cisplatin (CP) is a standard chemotherapy agent for osteosarcoma (OS). CP induced apoptosis to varying extents and activated AKT and Chk1 in multiple p53 wild-type and p53-null OS cell lines. A Chk1 inhibitor increased CP-induced apoptosis in all OS cell lines regardless of p53 status. In contrast, an AKT inhibitor increased CP-induced apoptosis only in p53 wild-type OS cells, but not p53 nulll cells. The increased apoptosis in p53 wild-type cells was coincident with decreased p53 protein levels, but increased expression of p53-responsive apoptotic genes Noxa and PUMA. Further studies revealed the inability of AKT inhibitor to CP-sensitize p53-null OS cells resulted from 2 things: 1) AKT inhibition stabilized/maintained p27 levels in CP-treated cells, which then mediated a protective G1-phase cell cycle arrest, 2) AKT inhibition increased the levels of activated Chk1. Finally, schedule dependent inhibition of AKT and Chk1 evaded the protective G1 arrest mediated by p27 and maximized CP-induced OS cell killing. These data demonstrate AKT and Chk1 activation promote survival in CP-treated OS cells, and that strategic, scheduled targeting of AKT and Chk1 can maximize OS cell killing by CP. |
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Keywords: | apoptosis AKT cisplatin Chk1 osteosarcoma p53 |
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