Episode-like pulse testosterone supplementation induces tumor senescence and growth arrest down-modulating androgen receptor through modulation of p-ERK1/2, pARser81 and CDK1 signaling: biological implications for men treated with testosterone replacement therapy
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Giovanni Luca Gravina1, Francesco Marampon1, Patrizia Sanità1, Claudio Festuccia5, Chiara Forcella1, Luca Scarsella5, Anna Jitariuc5, Antonella Vetuschi5, Roberta Sferra5, Alessandro Colapietro5, Eleonora Carosa1, Susanna Dolci4, Andrea Lenzi2 and Emmanuele A. Jannini3
1Department of Biotechnological and Applied Clinical Sciences, Laboratory of Prostate Onco-pathology and Experimental Endocrinology, University of L'Aquila, 67100 L'Aquila, Italy
2Department of Experimental Medicine, Chair of Endocrinology, Sapienza University of Rome, 00161 Rome, Italy
3Department of Systems Medicine, Chair of Endocrinology and Medical Sexology (ENDOSEX), Tor Vergata University of Rome, 00133 Rome, Italy
4Department of Biomedicine and Prevention, Section of Anatomy, Tor Vergata University of Rome, 00133 Rome, Italy
5Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy
Giovanni Luca Gravina, email: [email protected]
Keywords: testosterone; prostate cancer; androgens; hypogonadism; pulse treatment
Received: May 06, 2017 Accepted: November 01, 2017 Published: November 30, 2017
Despite the growing body of knowledge showing that testosterone (T) may not significantly affect tumor progression in hypogonadal patients treated for prostate cancer (Pca), the use of this hormone in this population still remains controversial. The effects of continuous or pulsed T stimulation were tested in vitro and in vivo on androgen-sensitive Pca cell lines in order to assess the differential biological properties of these two treatment modalities. Pulsed T treatment resulted in a greater inhibition than continuous T supplementation of tumor growth in vitro and in vivo. The effects of pulsed T treatment on tumor growth inhibition, G0/G1 cell cycle arrest, and tumor senescence was more pronounced than those obtained upon continuous T treatments. Mechanistic studies revealed that G0/G1 arrest and tumor senescence upon pulsed T treatment were associated with a marked decrease in cyclin D1, c-Myc and SKp2, CDK4 and p-Rb levels and upregulation of p27 and p-ERK1/2. Pulsed, but not continuous, T supplementation decreased the expression levels of AR, p-ARser81 and CDK1 in both cellular models. The in vitro results were confirmed in an in vivo xenografts, providing evidence of a greater inhibitory activity of pulsed supraphysiological T supplementation than continuous treatment, both in terms of tumor volume and decreased AR, p-ARser81, PSA and CDK1 staining. The rapid cycling from hypogonadal to physiological or supra-physiological T intraprostatic concentrations results in cytostatic and senescence effects in preclinical models of androgen-sensitive Pca. Our preclinical evidence provides relevant new insights in the biology of Pca response to pulsed T supplementation.
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