Naphtho[1,2-b]furan-4,5-dione disrupts Janus kinase-2 and induces apoptosis in breast cancer MDA-MB-231 cells.
Naphtho[1,2-b]furan-4,5-dione (NFD), prepared from 2-hydroxy-1,4-naphthoquinone and chloroacetaldehyde in an efficient one-pot reaction, exhibits an anti-carcinogenic effect. NFD-induced apoptosis in MDA-MB-231 cells, as indicated by the accumulation of sub-G1 population, externalization of phosphatidylserine, loss of mitochondrial membrane potential (DeltaPsim) with subsequent release of cytochrome c, and activation of both capase-9 and caspase-3. This correlated with up-regulation in Bax and Bad, and down-regulation of various anti-apoptotic proteins, including Bcl-2, Bcl-X(L), Mcl-1, and survivin in NFD-treated cells. In the analysis of signal transduction pathway, NFD suppressed the phosphorylation of JAK2 in MDA-MB-231 cells without altering the expression of JAK2 protein. Activation of STAT3, Src, and PI3K/Akt were also inhibited by NFD. Moreover, the JAK2 inhibitor AG490 blocked JAK2, STAT3, Src, PI3K, and Akt activation, whereas both Src inhibitor PP2 and PI3K inhibitor wortmannin did not affect JAK2 activation. This suggests that STAT3, Src, and PI3K/Akt are downstream molecules of the JAK2 signaling pathway. AG490 treatment also mimics the cytotoxic effects of NFD. Taken together, these results indicate that NFD disrupts JAK2 pathway and induces apoptosis in MDA-MB-231 cells.
Lin
Kuei-Li
KL
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC.
Su
Jung-Chen
JC
Chien
Ching-Ming
CM
Tseng
Chih-Hua
CH
Chen
Yeh-Long
YL
Chang
Long-Sen
LS
Lin
Shinne-Ren
SR
D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000187:drug effects / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism*; D009285:Naphthoquinones / Q000633:toxicity*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000633:toxicity; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C073873:naphtho(1,2-b)furan-4,5-dione; D019869:Phosphatidylinositol 3-Kinases; D053614:Janus Kinase 2; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt