Pirin, an Nrf2-Regulated Protein, Is Overexpressed in Human Colorectal Tumors

Abstract

The evolutionary conserved non-heme Fe-containing protein pirin has been implicated as an important factor in cell proliferation, migration, invasion, and tumour progression of melanoma, breast, lung, cervical, prostate, and oral cancers. Here we found that pirin is overexpressed in human colorectal cancer in comparison with matched normal tissue. The overexpression of pirin correlates with activation of transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and increased expression of the classical Nrf2 target NAD(P)H:quinone oxidoreductase 1 (NQO1), but interestingly and unexpectedly, not with expression of the aldo-keto reductase (AKR) family members AKR1B10 and AKR1C1, which are considered to be the most overexpressed genes in response to Nrf2 activation in humans. Using pharmacologic and genetic approaches to either downregulate or upregulate Nrf2, we show that pirin is regulated by Nrf2 in human and mouse cells and in the mouse colon in vivo. The small molecule pirin inhibitor TPhA decreased the viability of human colorectal cancer (DLD1) cells, but this decrease was independent of the levels of pirin. Our study demonstrates the Nrf2-dependent regulation of pirin and encourages the pursuit for specific pirin inhibitors.

Pirin Promotes the Progression of Non-Small-Cell Lung Cancer by Increasing ODC1 to Suppress Autophagy

“…17 While being expressed at a relatively low level in human normal tissues, pirin was found to be upregulated in various epithelial-derived cancers, thereby becoming functionally linked to malignant transformation. 18 For example, pirin promotes epithelial to mesenchymal transition-mediated cell migration and drug resistance by suppressing E-cadherin. 19 However, a detailed investigation of its role in NSCLC is lacking.…”

“…Pirin was reported to be an oxidative stress sensor protein located in the nucleus to regulate transcription . While being expressed at a relatively low level in human normal tissues, pirin was found to be upregulated in various epithelial-derived cancers, thereby becoming functionally linked to malignant transformation . For example, pirin promotes epithelial to mesenchymal transition-mediated cell migration and drug resistance by suppressing E-cadherin .…”

Streamlined Proteome-Wide Identification of Drug Targets Indicates Organ-Specific Engagement

“…However, subcellular proteomics studies have primarily found the protein to be exclusively located in the cytosol 38,39 . Dysregulation of Pirin has been reported to play a role in various tumorigenesis pathways and cancers such as melanoma and colorectal cancer for instance 40,41 . Corollary, Ibuprofen which is a nonsteroidal anti-inflammatory drug (NSAID), has been reported to potentially reduce risk significantly for colorectal cancer 42,43 .…”

Anti-Inflammatory Mechanisms of Dietary Flavones: Tapping into Nature to Control Chronic Inflammation in Obesity and Cancer

“…Indeed, genetic ablation of Nrf2 in mice is associated with increased tumor burden after carcinogen exposure, supporting its role in tumor prevention [ 134 , 135 ]. At the same time, Nrf2 is overexpressed in different tumor types [ 136 , 137 ] and can promote tumor growth and metastasis [ 138 ]. Furthermore, Nrf2 promoted cancer chemoresistance by stimulating the expression of ARE-dependent multidrug resistance genes and decreased the effectiveness of common chemotherapies such as doxorubicin, carboplatin, or cisplatin [ 139 , 140 ].…”