p21 CIP1/WAF1 -mediated partial senescence supports steroidogenesis and therapy resistance in primary prostate cancer cultures

ABSTRACT Background Progression of prostate cancer to castration-resistant disease is driven by early adaptive mechanisms that remain poorly defined. Increasing evidence suggests that senescence-associated programs and intratumoral steroidogenesis may contribute to therapeutic resistance, but their functional interplay in hormone-naïve disease is unclear. Methods Hormone-naïve primary prostate cancer cultures (hnPCs) were established from diagnostic biopsies and characterized for proliferation, therapeutic response, senescence markers, and steroidogenic gene expression. Functional relevance of CDKN1A was assessed by knockdown experiments. Public transcriptomic datasets from ETS fusion–negative, AR signaling inhibitor–naïve metastatic castration-resistant prostate cancer (mCRPC) were interrogated for clinical validation. Results hnPCs exhibited low proliferative capacity yet intrinsic resistance to androgen deprivation therapy and docetaxel. Most cultures displayed coordinated overexpression of CDKN1A/p21 CIP1 together with steroidogenic enzymes, particularly AKR1C3, alongside p16 INK4a expression and SA-β-galactosidase activity, consistent with a partial senescence-like state. CDKN1A depletion selectively reduced AKR1C3 expression and increased proliferation in a subset of cultures, indicating that p21 maintains specific senescence-associated features while permitting adaptive plasticity. Analysis of ETS fusion–negative, ARSI-naïve mCRPC tumors revealed positive correlations between CDKN1A and steroidogenic genes, supporting the translational relevance of this program. Conclusions These findings identify a previously underrecognized CDKN1A-associated partial senescence program that supports steroidogenic reprogramming, survival, and early therapeutic resistance in aggressive prostate cancer. This adaptive state may predispose tumors to progression toward castration resistance and represents a potential biomarker and therapeutic vulnerability in high-risk, ETS-negative disease.