Vitamin D analogues up-regulate p21 and p27 during growth inhibition of pancreatic cancer cell lines.
To obtain information regarding the growth-inhibitory effect of 1,25-dihydroxyvitamin D3 and its non-calcaemic analogue 22-oxa-1,25-dihydroxyvitamin D3 on pancreatic cancer cell lines, differences in the effects of G1-phase cell cycle-regulating factors were studied in vitamin D-responsive and non-responsive cell lines. Levels of expression of cyclins (D1, E and A), cyclin-dependent kinases (2 and 4) and cyclin-dependent kinase inhibitors (p21 and p27) were analysed by Western blotting after treatment with these compounds. In the responsive cells (BxPC-3, Hs 700T and SUP-1), our observations were: (1) marked up-regulation of p21 and p27 after 24 h treatment with 10(-7) mol l(-1) 1,25-dihydroxyvitamin D3 and 22-oxa-1,25-dihydroxyvitamin D3; and (2) marked down-regulation of cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors after 7 days' treatment. In non-responsive cells (Hs 766T and Capan-1), no such changes were observed. In conclusion, vitamin D analogues up-regulate p21 and p27 as an early event, which in turn could block the G1/S transition and induce growth inhibition in responsive cells.
Kawa
S
S
The Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
Nikaido
T
T
Aoki
Y
Y
Zhai
Y
Y
Kumagai
T
T
Furihata
K
K
Fujii
S
S
Kiyosawa
K
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D016213:Cyclins / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D002117:Calcitriol; C051883:maxacalcitol