Increased PTEN expression due to transcriptional activation of PPARγ by Lovastatin and Rosiglitazone

Teresi, Rosemary E.; Shaiu, Chung-Wai; Chen, Ching‐Shih; Chatterjee, Krishna; Waite, Kristin; Eng, Charis

doi:10.1002/ijc.21799

Cited by 108 publications

(102 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…32,33 Recently, it has been shown that PTEN is a downstream target gene for PPARg, 34 and upregulation of PTEN by PPARg ligands such as rosiglitazone was probably responsible for the anticancer effects of these ligands. 35 Our in vitro study showed that rosiglitazone barely altered the expression of PTEN when XIAP is present, whereas this agent could significantly upregulate the expression of PTEN when XIAP was knocked out (HCT116-XIAP 2/2 cells). These results suggest that the presence of XIAP may be important in counteracting the effect of tumor suppressor PTEN.…”

Section: Discussionmentioning

confidence: 79%

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Dai

Qiao

Chan

et al. 2008

Intl Journal of Cancer

View full text Add to dashboard Cite

Ligands for peroxisome proliferator-activated receptor gamma (PPARc) possess anticancer properties. However, the efficacy of PPARc ligands varies in different cancers. In colon cancer, the role of PPARc 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 PPARc ligand, has any synergistic anticancer effect with XIAP downregulation in colon cancer. Human colon cancer cell lines HCT116-XIAP 1/1 cells and HCT116-XIAP 2/2 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 2/2 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 PPARc by its ligand. Rosiglitazone induced marked upregulation of PTEN in HCT116-XIAP 2/2 cells, as well as in xenograft tumors derived from HCT116-XIAP 2/2 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.

show abstract

Section: Discussionmentioning

confidence: 79%

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Dai

Qiao

Chan

et al. 2008

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…For example, a recent study suggests that the coactivator amplified-in-breast cancer 3 is needed for the (21). Studies from our own group also indicate that responsiveness to rosiglitazone requires at least one functional PTEN allele such that tumors with homozygous PTEN deletions or promoter mutations would prove refractory to treatment (22). Furthermore, signaling cross-talk between PPARg and estrogen receptor could lead to differential effects of PPARg ligand activation in breast cancer (23,24).…”

Section: Discussionmentioning

confidence: 98%

Pilot Study of Rosiglitazone Therapy in Women with Breast Cancer: Effects of Short-term Therapy on Tumor Tissue and Serum Markers

Yee¹,

Williams²,

Wen³

et al. 2007

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: Peroxisome proliferator-activated receptor g (PPARg) is a steroid nuclear receptor that is activated by natural compounds such as specific fatty acids and synthetic drugs such as thiazolidinedione antidiabetic agents. Expressed in normal and malignant mammary epithelial cells, activation of PPARg is associated with antiproliferative effects on human breast cancer cells in preclinical studies. The purpose of this study was to test the hypothesis that PPARg ligand therapy might inhibit tumor growth and progression in human breast cancer. Experimental Design: We conducted a pilot trial of short-term (2-6 weeks) treatment with the thiazolidinedione rosiglitazone in 38 women with early-stage (T is -T 2 , N 0-1 , M 0 ) breast cancer, administered between the time of diagnostic biopsy and definitive surgery. Results: Short-term treatment with rosiglitazone (8 mg/d) did not elicit significant effects on breast tumor cell proliferation using Ki67 expression as a measure of cell proliferation and surrogate marker of tumor growth and progression. In pretreatment tumors notable for nuclear expression of PPARg by immunohistochemistry, down-regulation of nuclear PPARg expression occurred following rosiglitazone administration (P = 0.005). No PPARG mutations were identified, and the incidence of P12A and H446H polymorphisms did not differ relative to U.S. controls (P = 0.5). Treatment with rosiglitazone resulted in increased serum adiponectin (P < 0.001), decreased insulin levels (P = 0.005), and increased insulin sensitivity (P = 0.004). Rosiglitazone was well tolerated without serious adverse events. Conclusion: Our data indicate that short-term rosiglitazone therapy in early-stage breast cancer patients leads to local and systemic effects on PPARg signaling that may be relevant to breast cancer.

show abstract

“…Because several reports have indicated that PTEN may be a downstream effector of PPAR␥ (Lee et al, 2006;Teresi et al, 2006), we assessed the effects of PPAR␥ on PTEN activity in H2122 cells. No consistent effect of PPAR␥ on PTEN expression was detected by immunoblotting.…”

Section: Ppar␥ Inhibits Lung Tumorigenesis By Inhibition Of Cox-2 713mentioning

confidence: 99%

Antitumorigenic Effects of Peroxisome Proliferator-Activated Receptor-γ in Non-Small-Cell Lung Cancer Cells Are Mediated by Suppression of Cyclooxygenase-2 via Inhibition of Nuclear Factor-κB

et al. 2007

View full text Add to dashboard Cite

Pharmacological activators of peroxisome proliferator-activated receptor-␥ (PPAR␥) inhibit growth of non-small-cell lung cancer (NSCLC) cell lines in vitro and in xenograft models. Because these agents engage off-target pathways, we have assessed the effects of PPAR␥ by overexpressing the protein in NSCLC cells. We reported previously that increased PPAR␥ inhibits transformed growth and invasiveness and promotes epithelial differentiation in a panel of NSCLC expressing oncogenic K-Ras. These cells express high levels of cyclooxygenase-2 (COX-2) and produce high levels of prostaglandin E 2 (PGE 2 ). The goal of these studies was to identify the molecular mechanisms whereby PPAR␥ inhibits tumorigenesis. Increased PPAR␥ inhibited expression of COX-2 protein and promoter activity, resulting in decreased PGE 2 production. Suppression of COX-2 was mediated through increased activity of the tumor suppressor phosphatase and tensin homolog, leading to decreased levels of phospho-Akt and inhibition of nuclear factor-B activity. Pharmacological inhibition of PGE 2 production mimicked the effects of PPAR␥ on epithelial differentiation in three-dimensional culture, and exogenous PGE 2 reversed the effects of increased PPAR␥ activity. Transgenic mice overexpressing PPAR␥ under the control of the surfactant protein C promoter had reduced expression of COX-2 in type II cells and were protected against developing lung tumors in a chemical carcinogenesis model. These data indicate that high levels of PGE 2 as a result of elevated COX-2 expression are critical for promoting lung tumorigenesis and that the antitumorigenic effects of PPAR␥ are mediated in part through blocking this pathway.

show abstract

Increased PTEN expression due to transcriptional activation of PPARγ by Lovastatin and Rosiglitazone

Cited by 108 publications

References 51 publications

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Pilot Study of Rosiglitazone Therapy in Women with Breast Cancer: Effects of Short-term Therapy on Tumor Tissue and Serum Markers

Antitumorigenic Effects of Peroxisome Proliferator-Activated Receptor-γ in Non-Small-Cell Lung Cancer Cells Are Mediated by Suppression of Cyclooxygenase-2 via Inhibition of Nuclear Factor-κB

Contact Info

Product

Resources

About