Analysis of common gene expression patterns in four human tumor cell lines exposed to camptothecin using cDNA microarray: identification of topoisomerase-mediated DNA damage response pathways.
Camptothecin (CPT) is a potent inhibitor of DNA topoisomerase I with a wide spectrum of anti-tumor activity. Relatively little information is available regarding the relation of known topoisomerase-mediated DNA damage with other intracellular pathways. To gain an insight into the intracellular molecular mechanisms of Topoisomerase I inhibitor camptothecin-mediated DNA damage leading to cell death, we used a high-density cDNA microarray to assess sensitive early gene expression profiles in SGC7901 (gastric cancer), Hela (cervical adenocarcinoma), K562 (chronic myelogenous leukemia) and HL60 (promyelocytic leukemia) tumor cells stimulated with camptothecin for 1 h at the concentrations of GI50 (50 % growth inhibition after 24 h of treatment). Analysis of the differentially expressed genes obtained 29 response genes common to all four cell lines. Moreover, these cell lines also shared the direction of regulation. Most of these common response genes were functionally related to cell proliferation or apoptosis, and some of them were involved in ATM (ataxia-telangiectasia mutated) and ATR (ATM-and Rad3 related) checkpoint pathways, JNK (c-Jun N-terminal kinase) pathway, the survival phosphatidylinositol (PI) 3 kinase-Akt-dependent pathway, mitochondrial cell death pathway, endoplasmic reticulum (ER)-related cell death pathway, and to ubiquitin/proteasome dependent protein degradation pathway. The data provides evidence for a linkage between topoisomerase-mediated DNA damage and intracellular signaling events, which may facilitate our understanding of the camptothecin mediated molecular mechanisms of action.
Guo
XueQing
X
State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai 200433, People's Republic of China.
Zhang
JunPing
J
Fu
XuPing
X
Wei
Qing
Q
Lu
YingHua
Y
Li
Yao
Y
Yin
Gang
G
Mao
YuMin
Y
Xie
Yi
Y
Rui
YaoCheng
Y
Ying
Kang
K
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D002166:Camptothecin / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis; D025801:Ubiquitin / Q000737:chemistry
D000972:Antineoplastic Agents, Phytogenic; D064007:Ataxia Telangiectasia Mutated Proteins; D002166:Camptothecin; D018797:Cell Cycle Proteins; D004264:DNA Topoisomerases, Type I; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D048670:MAP Kinase Kinase 4; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C576324:ATM protein, human; C576597:ATR protein, human