Analysis of gene expression profiles in human HL-60 cell exposed to cantharidin using cDNA microarray.
Cantharidin is a natural toxin that has antitumor properties and causes leukocytosis as well as increasing sensitivity of tumor cells resistant to other chemotherapeutic agents. There is limited information, however, on the molecular pharmacological mechanisms of cantharidin on human cancer cells. We have used cDNA microarrays to identify gene expression changes in HL-60 promyeloid leukemia cells exposed to cantharidin. Cantharidin-treated cells not only decreased expression of genes coding for proteins involved in DNA replication (e.g., DNA polymerase delta), DNA repair (e.g., FANCG, ERCC), energy metabolism (e.g., isocitrate dehydrogenase alpha, ADP/ATP translocase), but also decreased expression of genes coding for proteins that have oncogenic activity (e.g., c-myc, GTPase) or show tumor-specific expression (e.g., phosphatidylinositol 3-kinase). In contrast, these treated cells overexpressed several genes that encode intracellular and secreted growth-inhibitory proteins (e.g., BTG2, MCP-3) as well as proapoptotic genes (e.g., ATL-derived PMA-responsive peptide). Our findings suggest that alterations in specific genes functionally related to cell proliferation or apoptosis may be responsible for cantharidin-mediated cytotoxicity. We also found that exposure of HL-60 cells to cantharidin resulted in the decreased expression of multidrug resistance-associated protein genes (e.g., ABCA3, MOAT-B), suggesting that cantharidin may be used as an oncotherapy sensitizer, and the increased expression of genes in modulating cytokine production and inflammatory response (e.g., NFIL-3, N-formylpeptide receptor), which may partly explain the stimulating effects on leukocytosis. Our data provide new insight into the molecular mechanisms of cantharidin.
Zhang
Jun-Ping
JP
Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China.
Ying
Kang
K
Xiao
Zhen-Yu
ZY
Zhou
Bin
B
Huang
Qing-Shan
QS
Wu
Hong-Mei
HM
Yin
Ming
M
Xie
Yi
Y
Mao
Yu-Min
YM
Rui
Yao-Cheng
YC
D002193:Cantharidin / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020869:Gene Expression Profiling / Q000379:methods*; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D002193:Cantharidin