Isoalvaxanthone inhibits colon cancer cell proliferation, migration and invasion through inactivating Rac1 and AP-1.
Isoalvaxanthone (IAX) is a bioactive xanthone isolated from Cudrania cochinchinensis (Lour.). However, the function and mechanism of this compound in cancer migration and invasion have not been elucidated to date. In this study, we found that IAX could suppress various steps of tumor metastasis including proliferation, migration and invasion in a dose-dependent manner on colorectal cancer cells. Especially matrix metalloproteinase 2 (MMP-2), the pivotal factor in cancer invasion, was suppressed both on activation and expression after treated with IAX. To understand the underlying mechanism of IAX on the inhibitory effect of proliferation, migration and invasion, we demonstrated that IAX could significantly inhibit the activation of Rac1 but has undetectable effect on GTP-RhoA, GTP-Cdc42 and the phosphorylation of ERK1/2, p38 MAPK and JNK. Moreover, IAX showed little influence on the transcriptional activity of nuclear transcription factor kappaB (NF-kappaB) but strongly inhibited that of activator protein-1 (AP-1), which is the downstream transcriptional factor of Rac1. Together, our results indicate that IAX exerts anticancer effect in SW620 cells by targeting MMP-2 via regulating the activity of Rac1 and AP-1. These results are the first to reveal the function of IAX in tumor metastasis and its underlying molecular mechanism, thus suggest IAX to be a promising antimetastatic agent.
Wang
Lei
L
The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Kuang
Lisha
L
Pan
Xinhua
X
Liu
Junchen
J
Wang
Qian
Q
Du
Bing
B
Li
Dali
D
Luo
Jian
J
Liu
Mingyao
M
Hou
Aijun
A
Qian
Min
M
D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D029586:Moraceae / Q000737:chemistry; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D018517:Plant Roots / Q000737:chemistry; D010946:Plants, Medicinal / Q000737:chemistry; D011554:Pseudopodia / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044004:Xanthones / Q000302:isolation & purification / Q000494:pharmacology*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
D016328:NF-kappa B; C107953:RAC1 protein, human; D018808:Transcription Factor AP-1; D044004:Xanthones; C551412:isoalvaxanthone; D008156:Luciferases; D020830:rac1 GTP-Binding Protein