Anti-proliferative and pro-apoptotic effects of 3,3'-diindolylmethane             in human cervical cancer cells.
The antitumor effects of Indo-3-carbinol (I3C) have been proven in many             human carcinoma cells. However, the roles of 3,3-diindolylmethane (DIM), an important             polymer converted from I3C under pH 5.0-7.0, on the growth and proliferation of             cervical cancer HeLa and SiHa cells still remain unrevealed. In the present study,             we investigated the potential anti-proliferative and pro-apoptotic effects of             DIM on HeLa and SiHa cells. Cell proliferation was detected by Cell Counting kit-8             and apoptosis was analyzed by flow cytometry. In addition, morphological changes             accompanying cell apoptosis were observed using an inverted microscope after Hoechst             33258 staining. In addition, expression changes of proteins involved in the MAPK             and PI3K pathways were determined by western blotting. DIM treatment inhibited             the proliferation and induced apoptosis of HeLa and SiHa cells significantly in             a time- and dose-dependent manner. Moreover, SiHa cells were more sensitive to             DIM treatment than HeLa cells (P<0.05). In addition, the expression of ERK,             p38 and p-p38, which are involved in the MAPK pathway, was downregulated by DIM             treatment. Another protein involved in the MAPK pathway, JNK, was upregulated.             Furthermore, DIM treatment significantly suppressed the expression of Akt, p-Akt,             PI3K p110α, PI3K p110β, PI3K class III, GSK3-β, p-PDK1 and p-c-Raf which are involved             in the PI3K pathway. These results demonstrate that DIM exerts antitumor effects             on HeLa and SiHa cells through its anti-proliferative and pro-apoptotic roles,             especially for SiHa cells. The molecular mechanism for these effects may be related             to its regulatory effects on MAPK and PI3K pathway and apoptosis proteins. DIM             may be a preventive and therapeutic agent against cervical cancer.
Department of Gynecology, Renmin Hospital of Wuhan University, Wuchang, Wuhan 430060, PR China. zhujunyong1974@163.com
Junyong
J
Zhu
Yuan
Y
Li
Chao
C
Guan
Zuhua
Z
Chen
D000230:Adenocarcinoma / Q000188:drug therapy*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C000631429:PDK1 protein, human; C016392:3,3'-diindolylmethane