Targeting PPARγSignaling Cascade for the Prevention and Treatment of Prostate Cancer

Abstract

The peroxisome proliferator-activated receptor-gamma (PPARγ) is a member of the hormone-activated nuclear receptor superfamily. PPARγ can be activated by a diverse group of agents, such as endogenous polyunsaturated fatty acids, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), and thiazolidinedione (TZD) drugs. PPARγ induces antiproliferative, antiangiogenic, and prodifferentiation pathways in several tissue types, thus making it a highly useful target for downregulation of carcinogenesis. These TZD-derived novel therapeutic agents, alone or in combination with other anticancer drugs, have translational relevance in fostering effective strategies for cancer treatment. TZDs have been proven for antitumor activity in a wide variety of experimental cancer models, both in vitro and in vivo, by affecting the cell cycle, inducing cell differentiation and apoptosis, as well as by inhibiting tumor angiogenesis. Angiogenesis inhibition mechanisms of TZDs include direct inhibition of endothelial cell proliferation and migration, as well as reduction in tumor cell vascular endothelial growth factor production. In prostate cancer, PPARγ ligands such as troglitazone and 15d-PGJ2 have also shown to inhibit tumor growth. This paper will focus on current discoveries in PPARγ activation, targeting prostate carcinogenesis as well as the role of PPARγ as a possible anticancer therapeutic option. Here, we review PPARγ as an antitumor agent and summarize the antineoplastic effects of PPARγ agonists in prostate cancer.

Sleeping Beautyscreen revealsPpargactivation in metastatic prostate cancer

“…PPARG has been implicated in adipocyte differentiation, functioning as a critical link between lipid and carbohydrate metabolism (19). The role of PPARG1 (isoform 1) role in cancer biology is poorly characterized, with both tumor suppressing and oncogenic effects reported (20,21). PPARG2 (isoform 2) is expressed at negligible levels in murine tumors and human cell lines, at both the mRNA and protein levels (18).…”

A Meta-analysis of the Association of <i>PPAR</i>γ rs1801282 Polymorphism and NSAID Usage with the Risk of Developing Cancer

“…8,9) Studies suggest that PPARγ activation inhibits the proliferation of malignant cells from different lineages such as liposarcoma, breast adenocarcinoma, prostate carcinoma, colorectal carcinoma, non-small-cell lung carcinoma, pancreatic carcinoma, bladder cancer, and gastric carcinoma. 10) Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce inflammation by decreasing the synthesis of prostaglandin (PG), and inhibiting NF-κB and PPARγ activation. [11][12][13] NSAIDs are one of the most widely used medicines for the prevention and/ or treatment of various diseases.…”

“…3,14) Activation of PPARγ inhibits the production of inflammatory cytokines [4][5][6][7] and the proliferation of malignant cells. 10) NSAIDs reduce inflammation by activating PPARγ. [11][12][13] Therefore, it is thought that the PPARγ rs1801282 polymorphism influences cancer risk in conjunction with NSAID usage.…”

Troglitazone inhibits the migration and invasion of PC‑3 human prostate cancer cells by upregulating E‑cadherin and glutathione peroxidase 3

“…PPARγ has been investigated as a therapeutic target for cancer treatment. Certain previous studies have reported that PPARγ is able to induce anti-proliferative, anti-angiogenic and pro-differentiation signaling pathways in specific tissue types, thus serving a role in the pathogenesis and progression of various types of cancer, including prostate cancer (24,25). Using TZDs as PPARγ ligands, previous studies have investigated the effect of PPARγ on the metastatic potential and investigated its underlying mechanisms (26)(27)(28)(29)(30)(31)(32)(33)(34).…”