FKBP4 regulates 5-fluorouracil sensitivity in colon cancer by controlling mitochondrial respiration

Abstract

Mitochondrial respiration and metabolism play a key role in the pathogenesis and progression of colon adenocarcinoma (COAD). Here, we report a functional pool of FKBP4, a co-chaperone protein, in the mitochondrial intermembrane space (IMS) of colon cancer cells. We found that IMS-localized FKBP4 is essential for the maintenance of mitochondrial respiration, thus contributing to the sensitivity of COAD cells to 5-fluorouracil (5-FU). Mechanistically, FKBP4 interacts with COA6 and controls the assembly of the mitochondrial COA6/SCO1/SCO2 complex, thereby governing COA6-regulated biogenesis and activity of mitochondrial cytochrome c oxidase (complex IV). Thus, our data reveal IMS-localized FKBP4 as a novel regulator of 5-FU sensitivity in COAD, linking mitochondrial respiration to 5-FU sensitivity in COAD.

Circular RNA circDDX17 suppression to gastric cancer progression via the sponging miR-1208/miR-1279/FKBP5 axis and encodes a novel circDDX17-63aa protein

“…The rst proteins of the immunosuppressive drug cyclosporin, that were found were cyclophilins and FK506 binding proteins (FKBPs) 38 . According to recent studies, immunophilins are crucial for the intrinsic characteristics of a tumor [39][40][41] . The FKBP5 gene was the only immunophilin family member to be found to have a splicing variation 42 .…”

Impact ofFKBP52on cell proliferation and hormone‐dependent cancers

“… 83 , 84 Although the knockdown of FKBP52 did not affect the growth of colon adenocarcinoma cell lines, increased sensitivity to 5‐fluorouracil was observed in FKBP52‐KD cells. 83 Additionally, FKBP4 was transcriptionally activated by E2F1. 84 The expression of FKBP52 is also increased in lung adenocarcinoma and is a poor prognostic factor for the disease.…”

“…Database analysis revealed that FKBP52 expression is increased in colorectal cancer 83,84 . Although the knockdown of FKBP52 did not affect the growth of colon adenocarcinoma cell lines, increased sensitivity to 5‐fluorouracil was observed in FKBP52‐KD cells 83 . Additionally, FKBP4 was transcriptionally activated by E2F1 84 .…”

“…Prostate cancer Upregulated 37,68 Inhibition of proliferation 38 Upregulates AR dimerization 38 Breast cancer (ERα + ) Upregulated 46,77 Inhibition of proliferation 46 Upregulates ERα stability 46 Breast cancer (ERα − ) Upregulated 77,80 Inhibition of proliferation 80 Upregulates PI3K/AKT pathway 80 Colon cancer Upregulated 83,84 No effect 83 Resistance to 5-FU 83 Lung cancer Upregulated 56,85 Inhibition of proliferation 56,85 Upregulates PI3K/AKT pathway 85 Upregulates IKK/NF-κB pathway 56 Liver cancer Upregulated 86 No data No data…”

Scaffold proteins of cancer signaling networks: The paradigm of FK506 binding protein 51 (FKBP51) supporting tumor intrinsic properties and immune escape

“…The growing list of human syndromes associated with the immunophilin defect underscores the biological relevance of these proteins [ 20 – 23 ]. Immunophilins are largely opportunistically exploited by cancer cells to support and enable the tumor’s intrinsic properties [ 23 – 30 ]. For a comprehensive review of immunophilins as dynamic scaffolding elements in diverse signaling complexes, see [ 19 ].…”