Ligands for
peroxisome proliferator-activated receptor gamma (
PPAR gamma) possess anticancer properties. However, the efficacy of
PPAR gamma ligands varies in different
cancers. In
colon cancer, the role of
PPAR gamma and its
ligands is controversial. We recently showed that downregulation of
X-linked inhibitor of apoptosis protein (XIAP) could sensitize
colon cancer cells to
troglitazone, and 15-deoxy-D12,14-prostaglandin J2 (15-PGJ2) induced cell killing. In our study, we aimed to examine whether
rosiglitazone, another more clinically relevant
PPAR gamma ligand, has any synergistic anticancer effect with XIAP downregulation in
colon cancer. Human
colon cancer cell lines HCT116-XIAP(+/+) cells and HCT116-XIAP(-/-) cells were treated with various concentrations of
rosiglitazone. The effects of
rosiglitazone on cell proliferation, apoptosis and growth of xenograft
colon cancers were studied.
Rosiglitazone barely suppressed the growth and only very weakly induced apoptosis in HCT116 cells in vitro. Loss of XIAP did not sensitize HCT116 cells to
rosiglitazone-induced growth inhibition or apoptosis. In vivo studies revealed that
rosiglitazone strongly suppressed the growth of xenograft
colon cancer, especially
tumors derived from HCT116-XIAP(-/-) cells. The
rosiglitazone-treated
tumor had reduced expression of ki-67 and lowered mitotic rate. Downregulation of XIAP was associated with an impaired activation of
PPAR gamma by its
ligand.
Rosiglitazone induced marked upregulation of PTEN in HCT116-XIAP(-/-) cells, as well as in xenograft
tumors derived from HCT116-XIAP(-/-) cells. We concluded that
rosiglitazone significantly suppresses the growth of xenograft
colon cancer, and downregulation of XIAP sensitizes the xenograft
tumors to
rosiglitazone-induced
tumor suppression in vivo via upregulation of PTEN.