Inhibition of mouse embryonic carcinoma cell growth by lidamycin through down-regulation of embryonic stem cell-like genes Oct4, Sox2 and Myc.
Lidamycin (LDM, also known as C-1027) as an anti-cancer agent inhibits growth in a variety of cancer cells by inducing apoptosis and cell cycle arrest. In this study we demonstrated that inhibition of mouse embryonic carcinoma (EC) cell growth using LDM at low concentrations can be attributed to a loss of the cell's self-renewal capability but not to apoptosis or cell death, which can be correlated to the down-regulation of embryonic stem (ES) cell-like genes Oct4, Sox2 and c-Myc. MTT assays showed that LDM inhibited the growth of mouse P19 EC cells in a time- and dose-dependent manner. The EC cells exposed to a low dose (0.01 nM) of LDM lost their capability to generate colonies, as evidenced by the colony forming assay. Flow cytometer analyses demonstrated that LDM induced G1 arrest in exposed EC cells without apoptosis. Real-time qPCR, Western blotting and immunocytochemistry revealed that Oct4, Sox2 and c-Myc were down-regulated in LDM-exposed EC cells, but not adriamycin (ADM)-exposed cells. Furthermore, a combination of the low dose of LDM and ADM significantly reduced the proliferation of the cancer cells than single-agent treatment. This suggested that synergy of ADM and LDM improved chemotherapy. Taking together, our results indicate that LDM can reduce the capability for self-renewal that mouse EC cells possess through the repression of ES cell-like genes, thereby inhibiting carcinoma cell growth. This data also suggests that LDM might have potential for application in CSC-based therapy and be a useful tool for studying ES cell pluripotency and differentiation.
Zhen
Hong-Ying
HY
Department of Cell Biology, Peking University Health Sciences Center, Xue Yuan Road 38, Beijing, 100191, People's Republic of China. hyzhen@bjmu.edu.cn
He
Qi-Hua
QH
Zhen
Yong-Zhan
YZ
Wang
Shu-Ling
SL
Liu
Yi-Nan
YN
Wu
Wei-Hua
WH
Zhang
Xiao-Yan
XY
Lu
Ai-Li
AL
Shen
Li
L
D000617:Aminoglycosides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D054278:Embryonal Carcinoma Stem Cells / Q000187:drug effects* / Q000378:metabolism; D053281:Enediynes / Q000008:administration & dosage / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000235:genetics; D013997:Time Factors
D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D050814:Octamer Transcription Factor-3; D016271:Proto-Oncogene Proteins c-myc; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C058024:C 1027; D004317:Doxorubicin