Work

Cytoplasmic FKBP7 reflux sustains NFE2L1 levels in an adaptive response to chemotherapy in prostate cancer cells

Year: 2026

Type: preprint

Abstract: Understanding how cancer cells adapt to chemotherapy is essential for overcoming drug resistance. Here, we identify a mechanism of taxane resistance in prostate cancer mediated by FKBP7, a poorly characterized cis-trans prolyl isomerase resident in the endoplasmic reticulum (ER). Using cell fractionation, we show that FKBP7 undergoes proteasome-independent retrotranslocation from the ER to the cytosol. This cytosolic pool is increased in docetaxel-resistant cells, which have also developed an enhanced capacity to counteract chemotherapy-induced oxidative stress. In the cytosol, FKBP7 associates with the translation machinery, interacting with multiple regions of the scaffolding protein eIF4G1, including its C-terminal HEAT3 domain, as well as with the 40S ribosomal subunit and polysomes. Polysome profiling and RNA sequencing after FKBP7 silencing revealed that FKBP7 loss leads to translation buffering of a large set of mRNAs, many of which are targets of the transcription factor NFE2L1, a master regulator of the oxidative stress response. Consistently, FKBP7 sustained NFE2L1 protein levels, and both proteins were required for the survival of docetaxel-resistant cells. Pharmacological inhibition of NFE2L1 activation suppressed the growth of docetaxel-resistant cells. We further report the first structural characterization of the FKBP7 catalytic domain by NMR, showing that it is a well-folded protein that binds rapamycin and everolimus, but not FK506. Together, these findings uncover a moonlighting function for an ER-resident chaperone in cytosolic translational control and oxidative stress adaptation and identify the FKBP7-NFE2L1 axis as a potential therapeutic target to overcome chemoresistance.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.01.18.700172