Phorbol 12-myristate 13-acetate inhibits FRO anaplastic human thyroid cancer cell proliferation by inducing cell cycle arrest in G1/S phase: evidence for an effect mediated by PKCdelta.
Phorbol 12-myristate 13-acetate (PMA) is known to affect a variety of cellular processes, including cell proliferation, differentiation, and migration. PMA has been shown to promote antiproliferative and antimigratory effects in many types of cancer cells. Our findings show that PMA induced a strong antiproliferative effect in two anaplastic (FRO and ARO) and one follicular (ML-1) thyroid cancer cell lines, and increased the fraction of FRO cells in G1 phase of the cell cycle. The fractions in the S and G2 phases were decreased. Moreover, PMA evoked a significant increase in the levels of the cell cycle regulators p21Waf1/Cip1 and p27Kip1. The levels of cyclin D3 and the cyclin-dependent kinases cdk4 and cdk6 decreased, as did the phosphorylation of the Rb-protein. PMA did not induce apoptosis. PMA stimulated the translocation of protein kinase C (PKC) alpha, betaI and delta isoforms to the cell membrane. PKCdelta small interfering RNA attenuated the PMA-induced antiproliferative effect and prevented the upregulation of p21Waf1/Cip1 and p27Kip1. Prolonged stimulation with PMA decreased the phosphorylation of mitogen-activated protein (MAP) kinase. PMA also decreased the phosphorylation of Akt and evoked a biphasic change in the phosphorylation of the forkhead box class-O protein (FOXO): an increase in phosphorylation, followed by a dephosphorylation. In addition, PMA inhibited FRO, ARO and ML-1 cell migration toward serum. The inactive phorbol ester analog 4alpha-phorbol and the diacylglycerol analog 1,2-dioctanoyl-sn-glycerol were without an effect on proliferation and migration. The results indicate that PMA is an effective inhibitor of thyroid cancer cell proliferation and migration by a mechanism involving PKC-MAP kinase/Akt and FOXO signaling.
Department of Biology, Abo Akademi University, BioCity, Artillerigatan 6, 20520 Turku, Finland.
Emad
E
Afrasiabi
Janiina
J
Ahlgren
Nina
N
Bergelin
Kid
K
Törnquist
D002277:Carcinoma / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010704:Phorbols / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016196:S Phase / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013964:Thyroid Neoplasms / Q000201:enzymology* / Q000473:pathology*; D014162:Transfection
D050759:Cyclin-Dependent Kinase Inhibitor p21; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007527:Isoenzymes; D010704:Phorbols; D034741:RNA, Small Interfering; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051057:Proto-Oncogene Proteins c-akt; D051745:Protein Kinase C-delta; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate; C033085:phorbol