Hashimoto Koji, Ethridge Richard T, Evers B Mark
Department of Surgery, The University of Texas Medical Branch, Galveston, TX 77555-0536, USA.
Int J Gastrointest Cancer. 2002;32(1):7-22. doi: 10.1385/IJGC:32:1:7.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in certain human cancers; ligand-induced PPARgamma activation can result in growth inhibition and differentiation in these cells. However, the precise mechanism for the antiproliferative effect of PPARgamma ligands is not entirely known.
The purpose of this study was to examine the effect of PPARgamma ligands on pancreatic cancer cell growth and invasiveness.
The effect of two PPARgamma ligands, 15 deoxy-delta12,14 prostaglandin J2 (15d-PGJ2) and ciglitazone, on the growth of four human pancreatic cancer cell lines (BxPC-3, MIA PaCa-2, Panc-1, and L3.6) was assessed. Expression of cell-cycle and apoptotic-related proteins was measured. Finally, the effect of 15d-PGJ2 on pancreatic cancer cell invasiveness and matrix metalloproteinase expression was determined.
Both 15d-PGJ2 and ciglitazone inhibited the growth of all four pancreatic cancer cell lines in a dose- and time-dependent fashion. Treatment of BxPC-3 cells with 15d-PGJ2 resulted in a time-dependent decrease in cyclin D1 expression associated with a concomitant induction of p21waf1 and p27kip1. In addition, 15d-PGJ2 treatment induced apoptosis through activation of caspase-8, -9, and -3. Moreover, pancreatic cancer cell invasiveness was significantly suppressed after treatment with a nontoxic dose of 15d-PGJ2, which was associated with a reduction of MMP-2 and MMP-9 protein levels and activity.
These results demonstrate that PPARgamma ligands have the dual advantage of inhibiting pancreatic cancer cell growth while reducing the invasiveness of the tumor cells, suggesting a potential role for these agents in the adjuvant treatment of pancreatic cancer.
过氧化物酶体增殖物激活受体γ（PPARγ）在某些人类癌症中表达；配体诱导的PPARγ激活可导致这些细胞的生长抑制和分化。然而，PPARγ配体抗增殖作用的确切机制尚不完全清楚。
本研究旨在探讨PPARγ配体对胰腺癌细胞生长和侵袭性的影响。
评估两种PPARγ配体15-脱氧-Δ12,14-前列腺素J2（15d-PGJ2）和吡格列酮对四种人类胰腺癌细胞系（BxPC-3、MIA PaCa-2、Panc-1和L3.6）生长的影响。检测细胞周期和凋亡相关蛋白的表达。最后，确定15d-PGJ2对胰腺癌细胞侵袭性和基质金属蛋白酶表达的影响。
15d-PGJ2和吡格列酮均以剂量和时间依赖性方式抑制所有四种胰腺癌细胞系的生长。用15d-PGJ2处理BxPC-3细胞导致细胞周期蛋白D1表达随时间下降，同时伴随p21waf1和p27kip1的诱导。此外，15d-PGJ2处理通过激活半胱天冬酶-8、-9和-3诱导凋亡。此外，用无毒剂量的15d-PGJ2处理后，胰腺癌细胞的侵袭性显著受到抑制，这与MMP-2和MMP-9蛋白水平及活性的降低有关。
这些结果表明，PPARγ配体具有抑制胰腺癌细胞生长和降低肿瘤细胞侵袭性的双重优势，提示这些药物在胰腺癌辅助治疗中具有潜在作用。
