Hypoxia-inducible factor 1A inhibition overcomes castration resistance of prostate tumors.

Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone-independent state termed castration-resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of Pten mice, generated by luminal epithelial cell-specific deletion of the tumor suppressor PTEN after puberty, is castration-resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells.

Senescence controls prostatic neoplasia driven by Pten loss.

We report that Pten (phosphatase and tensin homologue) ablation in prostatic epithelial cells of adult mice promotes cell proliferation to generate prostatic intraepithelial neoplasia. Moreover, our results demonstrate that proliferating Pten-deficient cells undergo replication stress and exhibit a DNA damage response, leading to cell senescence, as seen in oncogene-induced senescence.

deletion in luminal cells of mature prostate induces replication stress and senescence in vivo.

Genetic ablation of the tumor suppressor in prostatic epithelial cells (PECs) induces cell senescence. However, unlike oncogene-induced senescence, no hyperproliferation phase and no signs of DNA damage response (DDR) were observed in -deficient PECs; loss-induced senescence (PICS) was reported to be a novel type of cellular senescence. Our study reveals that ablation in prostatic luminal epithelial cells of adult mice stimulates PEC proliferation, followed by a progressive growth arrest with characteristics of cell senescence.