Apr 1, 2020

SLX4IP-mediated telomere maintenance is essential for androgen receptor-independent castration-resistant prostate cancer

BioRxiv : the Preprint Server for Biology
T. L. MangoshDerek J Taylor

Abstract

In advanced prostate cancer, resistance to androgen deprivation therapy is achieved through numerous mechanisms, including loss of the androgen receptor (AR) allowing for AR-independent growth. Therapeutic options are limited for AR-independent castration-resistant prostate cancer, and defining mechanisms critical for its survival is of utmost importance for targeting this lethal disease. Our studies have focused on defining the telomere maintenance mechanism (TMM) required for castration-resistant prostate cancer (CRPC) cell survival. TMMs are responsible for telomere elongation to instill replicative immortality and prevent senescence, with the two TMM pathways available being telomerase and alternative lengthening of telomeres (ALT). Here, we show that AR-independent CRPC exhibits ALT hallmarks and limited telomerase expression and activity, whereas AR-dependent models use telomerase for telomere maintenance. AR-independent CRPC exhibited elevated levels of SLX4IP, a protein implicated in TMM switching. SLX4IP overexpression in AR-dependent CRPC C4-2B cells promoted ALT hallmarks in vitro. SLX4IP knockdown in AR-independent CRPC cells (DU145 and PC-3) led to the loss of ALT hallmarks, dramatic telomere shortening, induction ...Continue Reading

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Mentioned in this Paper

Study
Pathogenic Aspects
MRNA Maturation
Pathogenesis
Malignant Neoplasm of Spinal Cord
Antioxidants
Nerve Degeneration
Oxidative Stress
Biologic Development
Oxidative Stress Analysis

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