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

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.