Quantitative proteomics identifies STEAP4 as a critical regulator of mitochondrial dysfunction linking inflammation and colon cancer

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder and is a major risk factor for colorectal cancer (CRC). Hypoxia is a feature of IBD and modulates cellular and mitochondrial metabolism. However, the role of hypoxic metabolism in IBD is unclear. Because mitochondrial dysfunction is an early hallmark of hypoxia and inflammation, an unbiased proteomics approach was used to assess the mitochondria in a mouse model of colitis. Through this analysis, we identified a ferrireductase: six-transmembrane epithelial antigen of prostate 4 (STEAP4) was highly induced in mouse models of colitis and in IBD patients. STEAP4 was regulated in a hypoxia-dependent manner that led to a dysregulation in mitochondrial iron balance, enhanced reactive oxygen species production, and increased susceptibility to mouse models of colitis. Mitochondrial iron chelation therapy improved colitis and demonstrated an essential role of mitochondrial iron dysregulation in the pathogenesis of IBD. To address if mitochondrial iron dysregulation is a key mechanism by which inflammation impacts colon tumorigenesis, STEAP4 expression, function, and mitochondrial iron chelation were assessed in a colitis-associated colon cancer model (CAC). STEAP4 was increased in human CRC and predicted poor prognosis. STEAP4 and mitochondrial iron increased tumor number and burden in a CAC model. These studies demonstrate the importance of mitochondrial iron homeostasis in IBD and CRC.

Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis

“…Next, we sought to determine whether IL-17-induced STEAP4mediated cellular copper uptake contributes to colon cancer progression in human. Consistent with a previous report 46 , we found that STEAP4 was overexpressed in a subset of human colon cancer tissues and correlated with worse prognosis for human CRC ( Fig. 6a and Supplementary Fig.…”

“…Although the metallo-reductase activity of STEAP4 has been extensively characterized in vitro [29][30][31] , the pathophysiological function of STEAP4 has remained elusive. A recent study from Xue et al 46 has shown that STEAP4 overexpression in colonic epithelia cells increased the amount of iron in mitochondria at steady state and rendered mice susceptible to chemically induced colitis and colon tumorigenesis. By employing a loss-of-function approach, we found that both copper and iron accumulation were impaired in the colonic epithelial cell-specific STEAP4-deficient mice during the process of colon tumorigenesis.…”

Gut bacteria signaling to mitochondria in intestinal inflammation and cancer

“…Mice treated with dextran sodium sulfate (DSS) to induce colitis exhibited swollen mitochondria, increased mtROS generation, decreased ETC activity and ATP level in the colonic mucosa that was ameliorated by anti-TNFα treatment. 54,64 Mice with deletion of IRGM, a CD susceptibility gene that affects mitochondrial fission and induces autophagy, exhibited increased susceptibility to experimental colitis. 65,66 Polymorphisms in SLC22A5, which encodes OCTN2 the carnitine transporter involved in mitochondrial FAO, are associated with CD risk.…”

Intervention of oncostatin M-driven mucosal inflammation by berberine exerts therapeutic property in chronic ulcerative colitis

“…Sections were then post-fixed with 1% OsO 4 (Sigma-Aldrich) for 1 h and embedded in resin. Ultra-thin sections (70 nm) in each group were prepared and stained as previous description 29 . The structures of colonic sections were observed using TEM (Philips Tecnai 20 U-Twin, Holland).…”