1,25-Dihydroxycholecalciferol (1,25-D3) inhibits the growth of squamous cell carcinoma and down-modulates p21(Waf1/Cip1) in vitro and in vivo.
1,25-Dihydroxycholecalciferol (1,25-D3) has significant antitumor effects in the murine squamous cell carcinoma (SCC) tumor model in vitro and in vivo. We investigated the basis for this antiproliferative activity and found that, in vitro, 1,25-D3 administration is associated with altered expression of cell cycle regulatory proteins, treatment results in retinoblastoma dephosphorylation, decreased expression of p21(Waf1/Cip1) (p21) mRNA and protein, and increased expression of p27Kip1 (p27) mRNA and protein. Dexamethasone, which acts synergistically with 1,25-D3 to inhibit SCC proliferation, enhanced 1,25-D3-induced down-modulation of p21 without affecting the ability of 1,25-D3 to increase p27 expression. 1,25-D3 did not induce cleavage of poly(ADP-ribose) polymerase. These in vitro data suggest that 1,25-D3 exerts antitumor activity in SCC by perturbing cell cycle progression rather than by inducing apoptosis. In vivo, a 1,25-D3 treatment regimen that results in a decrease in SCC tumor volume is associated with a statistically significant decrease in intratumoral p21 expression. p21 expression is not changed in tumors isolated from control animals or animals treated with a nontherapeutic dose of 1,25-D3. Intratumoral p27 levels were not modulated by 1,25-D3 treatment. Thus, both in vitro and in vivo, 1,25-D3-mediated growth inhibition is associated with p21 down-modulation.
Hershberger
P A
PA
Department of Pharmacology, and The University of Pittsburgh Cancer Institute, University of Pittsburgh, Pennsylvania 15213, USA. pah13+@pitt.edu
Modzelewski
R A
RA
Shurin
Z R
ZR
Rueger
R M
RM
Trump
D L
DL
Johnson
C S
CS
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002117:Calcitriol / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D016193:G1 Phase / Q000187:drug effects*; D051379:Mice; D008809:Mice, Inbred C3H; D008840:Microfilament Proteins / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D016192:Resting Phase, Cell Cycle / Q000187:drug effects*; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D009363:Neoplasm Proteins; D016160:Retinoblastoma Protein; C058992:Tagln protein, mouse; D003907:Dexamethasone; D002117:Calcitriol