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

5-fluorouracil Colorectal cancer; metastasis Diabetes mellitus PPARG

Journal

BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800

Informations de publication

Date de publication:
20 Feb 2024
Historique:
received: 09 10 2023
accepted: 08 02 2024
medline: 21 2 2024
pubmed: 21 2 2024
entrez: 20 2 2024
Statut: epublish

Résumé

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.

Sections du résumé

BACKGROUND BACKGROUND
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.
MATERIAL AND METHODS METHODS
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.
RESULTS RESULTS
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.
CONCLUSION CONCLUSIONS
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.

Identifiants

DOI: 10.1186/s12885-024-11985-5 PMID: 38378472
pubmed: 38378472
doi: 10.1186/s12885-024-11985-5
pii: 10.1186/s12885-024-11985-5
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

234

Informations de copyright

© 2024. The Author(s).

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Auteurs

Leah Schöckel (L)

Institute of Pathology, Ludwig-Maximilians-University (LMU) München, Munich, Germany.

Christine Woischke (C)

Institute of Pathology, Ludwig-Maximilians-University (LMU) München, Munich, Germany.

Sai Agash Surendran (SA)

Institute of Pathology, Ludwig-Maximilians-University (LMU) München, Munich, Germany.

Marlies Michl (M)

Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.

Tobias Schiergens (T)

Department of General, Visceral and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany.

Andreas Hölscher (A)

Maria-Theresia-Klinik München, Munich, Germany.

Florian Glass (F)

Maria-Theresia-Klinik München, Munich, Germany.

Peter Kreissl (P)

District Hospital Ebersberg, Ebersberg, Germany.

Frederick Klauschen (F)

Institute of Pathology, Ludwig-Maximilians-University (LMU) München, Munich, Germany.
German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and LMU Munich Germany, Munich, Germany.

Michael Günther (M)

Institute of Pathology, Ludwig-Maximilians-University (LMU) München, Munich, Germany.
German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and LMU Munich Germany, Munich, Germany.
Innpath Institute for Pathology GmbH, Tirol Kliniken, Innsbruck, Austria.

Steffen Ormanns (S)

Institute of Pathology, Ludwig-Maximilians-University (LMU) München, Munich, Germany.
German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and LMU Munich Germany, Munich, Germany.
Innpath Institute for Pathology GmbH, Tirol Kliniken, Innsbruck, Austria.

Jens Neumann (J)

Institute of Pathology, Ludwig-Maximilians-University (LMU) München, Munich, Germany. jens.neumann@med.uni-muenchen.de.
German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and LMU Munich Germany, Munich, Germany. jens.neumann@med.uni-muenchen.de.

Classifications MeSH