A Novel Mechanism of PPARγ Regulation of TGFβ1: Implication in Cancer Biology

Abstract

Peroxisome proliferator-activated receptor-γ (PPARγ) and retinoic acid X-receptor (RXR) heterodimer, which regulates cell growth and differentiation, represses the TGFβ1 gene that encodes for the protein involved in cancer biology. This review will introduce the novel mechanism associated with the inhibition of the TGFβ1 gene by PPARγ activation, which regulates the dephosphorylation of Zf9 transcription factor. Pharmacological manipulation of TGFβ1 by PPARγ activators can be applied for treating TGFβ1-induced pathophysiologic disorders such as cancer metastasis and fibrosis. In this article, we will discuss the opposing effects of TGFβ on tumor growth and metastasis, and address the signaling pathways regulated by PPARγ for tumor progression and suppression.

Inhalation delivery of Telmisartan enhances intratumoral distribution of nanoparticles in lung cancer models

“…Further it is also speculated that AT 1 receptors are also involved in radiation induced fibrosis and in such conditions use of AT 1 receptor blockers may efficiently reduce tumor fibrosis. Our results support the concept that angiotensin receptor blockers with additional PPAR γ activation may be beneficial for controlling TGFβ1-induced tumor fibrosis and metastasis, because PPAR γ also regulates the tumor TGFβ1 expression as well as its activation [22]. …”

“…Moreover Tel has superior activity over Los possibly through PPAR γ activation. This is supported by the hypothesis that since TGF-β is involved in tumor fibrosis, use of ARBs with additional PPAR γ agonistic activity may show beneficial effects in abrogating the tumor fibrosis which in turn may increase the intratumoral distribution of nanotherapeutics [22]. Although, Los showed significant improvement in nanoparticle distribution and reduction in the lung tumor weights, due to lack of its PPAR γ activation ability, these effects were inferior to Tel.…”

“…Improvement of nanocarriers cancer-targeting therapy by inhibition of TGF-β signaling was also reported in intractable solid tumors [21]. Peroxisome Proliferator-Activated Receptor-γ (PPAR γ) activation also inhibited the tumor metastasis by antagonizing TGF-β and Smad3 [18, 22]. A recent study demonstrated that AT 1 receptor blocker Los through TGF-β inhibition improved the penetration and therapeutic efficacy of drug loaded nanoparticles [10].…”

Protein Degradation by the Ubiquitin-Proteasome Pathway and Organ Fibrosis

“…Recently, it has been reported that PPAR-is degraded via the UPS, although the responsible E3 ligase has not been identified [71,72], and its agonists inhibit the development of liver, kidney and skin fibrosis [73][74][75]. Because PPAR-is known as a transcriptional repressor of TGF- [76,77] (Fig. 2), the therapeutic potential of PPARagonists is supposed to be mediated by inhibition of TGFsignaling, at least partially.…”

“…At present, Vercade ® (bortezomib or PS-341), a proteasome inhibitor, has been used as one option of the treatment for multiple myeloma. One possible therapeutic strategy for fibrotic diseases may be combined therapies of proteasome inhibitors with the drugs that affect the TGF-pathway such as PPAR-agonists [76,77] or monoclonal antibodies against TGF- [95,96]. However, the significant problem of proteasome inhibitors as a therapeutic strategy of chronic diseases including fibrosis is the low specificity for each substrate.…”