Details

Autor(en) / Beteiligte

• Zhu, Bokai
• Khozoie, Combiz
• Ferry, Christina H.
• Markell, Lauren M.
• Bility, Moses T.
• Blazanin, Nicholas
• Glick, Adam B.
• Gonzalez, Frank J.

Titel

Abstract 2172: Anti-oncogenic role of peroxisome proliferator-activated receptor-α/β (PPARδ/α) involves inhibition of mitosis and regulation of Hras1-induced senescence

Ist Teil von

• Cancer research (Chicago, Ill.), 2012-04, Vol.72 (8_Supplement), p.2172-2172

Erscheinungsjahr

2012

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• Abstract Ligand activation of PPARδ/α inhibits chemically-induced skin tumorigenesis and Pparα/α-null mice exhibit enhanced chemically-induced skin tumorigenesis compared to wild-type mice. The mechanism that mediates inhibition of skin carcinogenesis by PPARδ/α is still being unraveled and was examined in this study. Ligand activation of PPARδ/α caused a negative selection against cells expressing higher levels of HRAS by inducing a mitotic block. Mitosis-related genes that are predominantly regulated by E2F were induced to a higher level in HRAS-expressing Pparα/α-null keratinocytes as compared to HRAS-expressing wild-type keratinocytes. Ligand activated PPARδ/α repressed expression of these genes by direct binding with p130/p107, facilitating nuclear translocation, and increasing promoter recruitment of p130/p107. In addition, co-treatment with a PPARδ/α ligand and various mitosis inhibitors increases the efficacy of increasing G2/M arrest. PPARδ/α is also required for HRAS-induced senescence and suppression of malignant conversion of benign papillomas. HRAS-expressing Pparα/α-null keratinocytes evade senescence by utilizing the PI3K-AKT rather than the MEK-ERK pathway. PPARδ/α positively regulates MEK-ERK pathway by maintaining RASGRP1 levels and negatively regulating the PI3K-AKT pathway by repressing ILK and PDPK1 expression. Heightened AKT activity increases endoplasmic reticulum (ER) stress in Pparα/α-null keratinocytes, which in turn helps maintain higher AKT activity, leading to evasion of senescence. In addition, enhanced HRAS activity increases the synthesis of endogenous PPARδ/α ligands, thus providing a PPARδ/α-dependent cell-autonomous mechanism to suppress HRAS-induced carcinogenesis. (Supported by CA124533). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2172. doi:1538-7445.AM2012-2172