Pioglitazone, a synthetic ligand for PPARγ, induces apoptosis in RB-deficient human colorectal cancer cells

Abstract

No published data are available about the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and the role of PPARgamma in retinoblastoma protein (RB)-deficient human colorectal cancer (CRC) cells (SNU-C4 and SNU-C2A). Our aim was to investigate whether PPARgamma is expressed in SNU-C4 and SNU-C2A cells and to elucidate possible molecular mechanisms underlying the effect of pioglitazone, a synthetic ligand for PPARgamma, on cell growth in these cell lines. RT-PCR and Western blot analysis showed that both human CRC cell lines expressed PPARgamma mRNA and protein. Pioglitazone inhibited the cell growth of both cell lines through G2/M phase block and apoptosis. In addition, pioglitazone caused a down-regulation of the X chromosome-linked inhibitor of apoptosis (XIAP), Bcl-2, and cyclooxygenase-2 (COX-2) under conditions leading to PPARgamma down-regulation. These results suggest that pioglitazone may have therapeutic relevance or significance in the treatment of human CRC, and the down-regulation of XIAP, Bcl-2, and COX-2 may contribute to pioglitazone-induced apoptosis in these and other RB-deficient cell lines and tumors.

Stichoposide C Induces Apoptosis through the Generation of Ceramide in Leukemia and Colorectal Cancer Cells and Shows In Vivo Antitumor Activity

“…Cell-cycle analysis was carried out on propidium iodide (PI)-stained samples (20); whereas the extent of apoptosis was evaluated by annexin V-fluorescein isothiocyanate (FITC) and flow cytometry, as previously described (21).…”

“…Cytosolic and mitochondrial proteins were separated as previously described (20,22). In brief, cells treated with 0.1% DMSO or with STC for indicated times were collected and resuspended in mitochondrial isolation buffer and protease inhibitor cocktail (Boehringer Mannheim) supplemented with 10 mmol/L digitonin.…”

“…To determine the in vivo activity of STC, viable HL-60 cells (2 Â 10 7 /100 mL PBS per mouse) and CT-26 cells (2 Â 10 6 /100 mL PBS per mouse), as confirmed by trypan blue staining, were injected into the right flank of 6-to 7-week-old female Balb/c nude mice and Balb/c mice, respectively (Orient Bio Inc.) as previously described (20). When average subcutaneous tumor volume reached 60 to 100 mm 3 , mice were assigned into 2 treatment groups: (i) control and (ii) STC, given at a dose of 7.19 mg/kg via tail vein every 3 days.…”

Peroxisome proliferator-activated receptor γ and colorectal cancer

“…In colon cancer cells, treatment with the PPARγ ligands (pioglitazone, troglitazone) upregulates the proapoptotic protein Bax and downregulates the antiapoptotic protein Bcl-2 [44][45][46] . Alternative expres-sion of Bax and Bcl-2 causes apoptosis by the release of cytochrome C and subsequent activation of several effector caspases.…”

The therapeutic implications of clinically applied modifiers of heat shock protein 70 (Hsp70) expression by tumor cells

“…COX-2 inhibitors also induce tumor cell apoptosis and inhibit cell proliferation (Patti et al 2002;Yamazaki et al 2002). We were, therefore, interested to test the effects of several non-steroidal antiinflammatory drugs and pioglitazone (PIO; Lee et al 2006), an insulin sensitizer with anti-inflammatory properties, on the expression of Hsp70 in human colon carcinoma cell lines, which exhibited differential Hsp70 membrane expression pattern . For these studies, colon cancer cells were treated with varying doses of the COX-1/COX-2 inhibitor aspisol (ASA), the COX-2 inhibitors celecoxib (CLX) and rofecoxib (RFX) and PIO.…”