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. 2018 Dec;9(6):2229-2243.
doi: 10.1007/s13300-018-0509-y. Epub 2018 Sep 25.

Association of Pioglitazone with Increased Risk of Prostate Cancer and Pancreatic Cancer: A Functional Network Study

Weiheng Wen  1 , Peili Wu  1 , Jinru Gong  2 , Min Zhao  1 , Zhen Zhang  1 , Rongping Chen  1 , Hong Chen  3 , Jia Sun  4
Affiliations

Association of Pioglitazone with Increased Risk of Prostate Cancer and Pancreatic Cancer: A Functional Network Study

Weiheng Wen et al. Diabetes Ther. 2018 Dec.

Abstract

Introduction: The question of whether pioglitazone, an antidiabetic drug, increases the risk of cancer has been debated for some time. Recent studies have shown that pioglitazone use can increase the risk of prostate cancer as well as pancreatic cancer. However, it is unclear whether pioglitazone is a causal risk factor for these cancers.

Methods: In this study, we aimed to explore the direct targets of pioglitazone and genes associated with this drug by querying open platforms in order to construct a biological function network, and then to further evaluate the relationships of pioglitazone with prostate cancer and pancreatic cancer.

Results: We first tested our hypothesis using DrugBank and STRING. We identified four direct targets of pioglitazone and 50 pioglitazone-associated genes, which were then selected for KEGG pathway analysis using STRING and WebGestalt. This analysis generated the top 25 KEGG pathways, among which four pathways were related to site-specific cancers, including prostate cancer and pancreatic cancer. Finally, a genomic study using cBioPortal indicated that genomic alterations of two gene sets related to the prostate cancer and pancreatic cancer pathways, respectively, are associated with the acceleration of carcinogenesis.

Conclusions: Pioglitazone is likely to be a causal risk factor for prostate cancer and pancreatic cancer, so this drug should be used with caution. The present research also demonstrates the use of biological function network analysis to effectively explore drug interactions and drug safety profiles.

Keywords: Bioinformatics; Cancer risk; Connectivity; Diabetic treatment; Drug safety; Functional network study; Pancreatic cancer; Pioglitazone; Prostate cancer; Side effect.

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Figures

Fig. 1
Fig. 1
Drug-target interactome of pioglitazone. The drug pioglitazone is highlighted in yellow, the primary direct protein targets (PPARA, PPARD, PPARG, and MAOB) are highlighted in red, and the secondary pioglitazone-associated proteins are highlighted in pink
Fig. 2
Fig. 2
KEGG pathway analysis of the potential functions of pioglitazone-associated genes in the pathway using STRING
Fig. 3a–b
Fig. 3a–b
Exploring the genetic alterations linked to the pioglitazone-related genes CREBBP, EP300, HSP90AA1, NFKB1, NFKBIA, MAPK1, RB1, and RELA in prostate cancer using cBioPortal. a Overview of variations in CREBBP, EP300, HSP90AA1, NFKB1, NFKBIA, MAPK1, RB1, and RELA in the genomic database across a series of prostate cancer samples. b Oncopoint: a visual display of genomic alterations in the eight identified genes (based on the Demichelis study [22]). Genomic alterations are summarized and displayed as % changes in the selected genes. Each row corresponds to a gene, and each column is a sample. Bars with different colors represent different genomic alterations
Fig. 4a–b
Fig. 4a–b
A visual display of gene networks linked to CREBBP/EP300/HSP90AA1/NFKB1/NFKBIA/MAPK1/RB1/RELA in prostate cancer (based on the Demichelis study [22]). a Eight selected pioglitazone-related genes were employed as seed genes (circles with thick black outlines) to harvest all the other genes that were changed in prostate cancer samples using cBioPortal. b Neighboring genes associated with the eight selected genes were filtered by alteration (%). Darker red indicates an increased frequency of alterations in prostate cancer. In addition to the selected genes, the filter used also involved the highest genomic alteration frequency in the prostate cancer study
Fig. 5a–b
Fig. 5a–b
Exploring genetic alterations linked to the pioglitazone-related genes RB1, MAPK1, NFKB1, RELA, and TGFB1 in pancreatic cancer using cBioPortal. a Overview of variations in RB1, MAPK1, NFKB1, RELA, and TGFB1 in the genomic database across a series of pancreatic cancer samples. b Oncopoint: a visual display of genomic alterations in the five identified genes (based on the Knudsen study [23])
Fig. 6a–b
Fig. 6a–b
A visual display of gene networks linked to RB1/MAPK1/NFKB1/RELA/TGFB1 in pancreatic cancer (based on the Knudsen study [23]). a Five selected pioglitazone-related genes to explore all the other genes that were changed in pancreatic cancer samples using cBioPortal. b Neighboring genes associated with the five selected genes were filtered by alteration (%)
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