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BMC Cancer

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PPARG activation promotes the proliferation of colorectal cancer cell lines and enhances the antiproliferative effect of 5-fluorouracil

Published:20 February 2024 DOI: 10.1186/s12885-024-11985-5
Leah Sch?ckel, Christine Woischke, Sai Agash Surendran, Marlies Michl, Tobias Schiergens, Andreas H?lscher, Florian Glass, Peter Kreissl, Frederick Klauschen, Michael Günther, Steffen Ormanns, Jens Neumann

Abstract

Peroxisome proliferator-activated receptor gamma (PPARG) is a member of the nuclear receptor family. It is involved in the regulation of adipogenesis, lipid metabolism, insulin sensitivity, vascular homeostasis and inflammation. In addition, PPARG agonists, known as thiazolidinediones, are well established in the treatment of type 2 diabetes mellitus. PPARGs role in cancer is a matter of debate, as pro- and anti-tumour properties have been described in various tumour entities. Currently, the specific role of PPARG in patients with colorectal cancer (CRC) is not fully understood. The prognostic impact of PPARG expression was investigated by immunohistochemistry in a case-control study using a matched pair selection of CRC tumours (n?=?246) with either distant metastases to the liver (n?=?82), lung (n?=?82) or without distant metastases (n?=?82). Its effect on proliferation as well as the sensitivity to the chemotherapeutic drug 5-fluorouracil (5-FU) was examined after activation, inhibition, and transient gene knockdown of PPARG in the CRC cell lines SW403 and HT29. High PPARG expression was significantly associated with pulmonary metastasis (p?=?0.019). Patients without distant metastases had a significantly longer overall survival with low PPARG expression in their tumours compared to patients with high PPARG expression (p?=?0.045). In the pulmonary metastasis cohort instead, a trend towards longer survival was observed for patients with high PPARG expression in their tumour (p?=?0.059). Activation of PPARG by pioglitazone and rosiglitazone resulted in a significant dose-dependent increase in proliferation of CRC cell lines. Inhibition of PPARG by its specific inhibitor GW9662 and siRNA-mediated knockdown of PPARG significantly decreased proliferation. Activating PPARG significantly increased the CRC cell lines sensitivity to 5-FU while its inhibition decreased it. The prognostic effect of PPARG expression depends on the metastasis localization in advanced CRC patients. Activation of PPARG increased malignancy associated traits such as proliferation in CRC cell lines but also increases sensitivity towards the chemotherapeutic agent 5-FU. Based on this finding, a combination therapy of PPARG agonists and 5-FU-based chemotherapy constitutes a promising strategy which should be further investigated.

Substances (8)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Rosiglitazone 122320-73-4 C18H19N3O3S 559 suppliers $8.00-$978.00
Rosiglitazone 122320-73-4 C18H19N3O3S 559 suppliers $8.00-$978.00
Rosiglitazone 122320-73-4 C18H19N3O3S 559 suppliers $8.00-$978.00
Rosiglitazone 122320-73-4 C18H19N3O3S 559 suppliers $8.00-$978.00
Pioglitazone 111025-46-8 C19H20N2O3S 303 suppliers $8.00-$1963.50
Pioglitazone 111025-46-8 C19H20N2O3S 303 suppliers $8.00-$1963.50
Pioglitazone 111025-46-8 C19H20N2O3S 303 suppliers $8.00-$1963.50
Pioglitazone 111025-46-8 C19H20N2O3S 303 suppliers $8.00-$1963.50

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