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

ABSTRACT Understanding how cancer cells adapt to chemotherapy is essential for overcoming resistance. One mechanism involved in taxane resistance in prostate cancer is mediated by FKBP7, a still-understudied endoplasmic reticulum-resident cis-trans isomerase. Using cell fractionation, we demonstrate that the ERAD-independent retrotranslocation of FKBP7 into the cytosol correlates with the oxidative stress triggered by chemotherapy, as an escape response. Once in the cytosol, FKBP7 interacts with the translation machinery and with eIF4G1, specifically with its C-terminal HEAT3 domain. Following FKBP7 silencing, polysome profiling and RNA sequencing identified the transcription factor NFE2L1 - a key regulator of oxidative stress adaptation - as an effector of FKBP7. Here, we also produced the first NMR spectra of the FKBP7 catalytic domain, revealing a well-folded protein that binds to rapamycin and everolimus but not to FK506. Overall, our results demonstrate that chemotherapy-induced oxidative stress triggers an adaptive mechanism in which FKBP7 is translocated into the cytosol where it modulates NFE2L1, thereby enabling the survival of resistant cells. These findings lead us to propose the targeting of FKBP7/NFE2L1 signaling as a strategy to overcome adaptive resistance.