title: Cyclic AMP (cAMP) confers drug resistance against DNA damaging agents via PKAIA in CML cells.
abstract: Cyclic adenosine monophosphate (cAMP) regulates many vital functions such as metabolism, proliferation, differentiation and death. Depending on cell types and stimulators, cAMP could either promote or attenuate cell death. cAMP signal can be transduced by protein kinase A (PKA) and/or exchange protein directly activated by cAMP (EPAC). In CML cells, cAMP may suppress their proliferation and enhance their differentiation. However, the role of cAMP on DNA damaging agent toxicity and the mechanism involved has not been studied. In this study, we studied the effect of cAMP on the sensitivity of CML cells to DNA damaging agents. We observed that forskolin (FSK) and dibutyryl-cAMP (DBcAMP) decreased cisplatin and etoposide-induced cell death in K562 cells. Moreover, PKA activator prevented K562 cells from DNA damaging agent-induced cell death while EPAC activator had no effect. Furthermore, we found that the PKA subtype, PKAIA, was involved in cAMP-attenuated resistance in K562 cells. Taken together, our results suggest that increased cAMP level confers CML cells to acquire a novel mechanism against DNA damaging agent toxicity via PKAIA. Thus, PKAIA inhibitor may be helpful in overcoming the resistance to DNA damaging agents in CML cells.
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Ling-Yi
authors.initials: LY
authors.lastname: Xiao
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. Electronic address: Vincent@mail.ncku.edu.tw.
authors.forename: Wai-Ming
authors.initials: WM
authors.lastname: Kan
mesh_terms: D003994:Bucladesine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology*; D054743:Cyclic AMP-Dependent Protein Kinase Type I / Q000378:metabolism*; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005576:Colforsin; D003994:Bucladesine; D005047:Etoposide; D000242:Cyclic AMP; D054743:Cyclic AMP-Dependent Protein Kinase Type I; D002945:Cisplatin
keywords: CML; DNA damaging agents; PKA; cAMP