Pregnane X-receptor promotes stem cell-mediated colon cancer relapse.
Planque C, Rajabi F, Grillet F, Finetti P, Bertucci F, Gironella M, Lozano JJ, Beucher B, Giraud J, Garambois V, Vincent C, Brown D, Caillo L, Kantar J, Pelegrin A, Prudhomme M, Ripoche J, Bourgaux JF, Ginestier C, Castells A, Hollande F, Pannequin J, Pascussi JM
Colorectal cancer lethality usually results from post-treatment relapse in the majority of stage II-IV patients, due to the enhanced resistance of Cancer Stem Cells (CSCs). Here, we show that the nuclear receptor Pregnane X Receptor (PXR, NR1I2), behaves as a key driver of CSC-mediated tumor recurrence. First, PXR is specifically expressed in CSCs, where it drives the expression of genes involved in self-renewal and chemoresistance. Clinically, high levels of PXR correlate with poor recurrence-free survival in a cohort of >200 stage II/III colorectal cancer patients treated with chemotherapy, for whom finding biomarkers of treatment outcome is an urgent clinical need. shRNA silencing of PXR increased the chemo-sensitivity of human colon CSCs, reduced their self-renewal and tumor-initiating potential, and drastically delayed tumor recurrence in mice following chemotherapy. This study uncovers PXR as a key factor for CSC self-renewal and chemoresistance and targeting PXR thus represents a promising strategy to minimize colorectal cancer relapse by selectively sensitizing CSCs to chemotherapy.Lire l‘article