Testosterone-mediated activation of androgenic signalling sustains in vitro the transformed and radioresistant phenotype of rhabdomyosarcoma cell lines

S Giannattasio, F Megiorni, V Di Nisio, A Del Fattore, R Fontanella, S Camero, C Antinozzi, C Festuccia, G L Gravina, S Cecconi, C Dominici, L Di Luigi, C Ciccarelli, P De Cesaris, A Riccioli, B M Zani, A Lenzi, R G Pestell, A Filippini, C CrescioliV Tombolini, F Marampon

Research output: Contribution to journalArticle

Abstract

PURPOSE: Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in childhood, rarely affects adults, preferring male. RMS expresses the receptor for androgen (AR) and responds to androgen; however, the molecular action of androgens on RMS is unknown.

METHODS: Herein, testosterone (T) effects were tested in embryonal (ERMS) and alveolar (ARMS) RMS cell lines, by performing luciferase reporter assay, RT-PCR, and western blotting experiments. RNA interference experiments or bicalutamide treatment was performed to assess the specific role of AR. Radiation treatment was delivered to characterise the effects of T treatment on RMS intrinsic radioresistance.

RESULTS: Our study showed that RMS cells respond to sub-physiological levels of T stimulation, finally promoting AR-dependent genomic and non-genomic effects, such as the transcriptional regulation of several oncogenes, the phosphorylation-mediated post-transductional modifications of AR and the activation of ERK, p38 and AKT signal transduction pathway mediators that, by physically complexing or not with AR, participate in regulating its transcriptional activity and the expression of T-targeted genes. T chronic daily treatment, performed as for the hormone circadian rhythm, did not significantly affect RMS cell growth, but improved RMS clonogenic and radioresistant potential and increased AR mRNA both in ERMS and ARMS. AR protein accumulation was evident in ERMS, this further developing an intrinsic T-independent AR activity.

CONCLUSIONS: Our results suggest that androgens sustain and improve RMS transformed and radioresistant phenotype, and therefore, their therapeutic application should be avoided in RMS post puberal patients.

Original languageEnglish
Number of pages15
JournalJournal of Endocrinological Investigation
DOIs
Publication statusE-pub ahead of print - May 22 2018

Fingerprint

Rhabdomyosarcoma
Androgens
Testosterone
Phenotype
Cell Line
Alveolar Rhabdomyosarcoma
In Vitro Techniques
Therapeutics
Androgen Receptors
Circadian Rhythm
RNA Interference
Luciferases
Oncogenes
Sarcoma
Signal Transduction
Western Blotting
Phosphorylation
Hormones
Radiation
Polymerase Chain Reaction

Cite this

Testosterone-mediated activation of androgenic signalling sustains in vitro the transformed and radioresistant phenotype of rhabdomyosarcoma cell lines. / Giannattasio, S; Megiorni, F; Di Nisio, V; Del Fattore, A; Fontanella, R; Camero, S; Antinozzi, C; Festuccia, C; Gravina, G L; Cecconi, S; Dominici, C; Di Luigi, L; Ciccarelli, C; De Cesaris, P; Riccioli, A; Zani, B M; Lenzi, A; Pestell, R G; Filippini, A; Crescioli, C; Tombolini, V; Marampon, F.

In: Journal of Endocrinological Investigation, 22.05.2018.

Research output: Contribution to journalArticle

Giannattasio, S, Megiorni, F, Di Nisio, V, Del Fattore, A, Fontanella, R, Camero, S, Antinozzi, C, Festuccia, C, Gravina, GL, Cecconi, S, Dominici, C, Di Luigi, L, Ciccarelli, C, De Cesaris, P, Riccioli, A, Zani, BM, Lenzi, A, Pestell, RG, Filippini, A, Crescioli, C, Tombolini, V & Marampon, F 2018, 'Testosterone-mediated activation of androgenic signalling sustains in vitro the transformed and radioresistant phenotype of rhabdomyosarcoma cell lines', Journal of Endocrinological Investigation. https://doi.org/10.1007/s40618-018-0900-6
Giannattasio, S ; Megiorni, F ; Di Nisio, V ; Del Fattore, A ; Fontanella, R ; Camero, S ; Antinozzi, C ; Festuccia, C ; Gravina, G L ; Cecconi, S ; Dominici, C ; Di Luigi, L ; Ciccarelli, C ; De Cesaris, P ; Riccioli, A ; Zani, B M ; Lenzi, A ; Pestell, R G ; Filippini, A ; Crescioli, C ; Tombolini, V ; Marampon, F. / Testosterone-mediated activation of androgenic signalling sustains in vitro the transformed and radioresistant phenotype of rhabdomyosarcoma cell lines. In: Journal of Endocrinological Investigation. 2018.
@article{94809a15712640d1b9713bf3e284d42d,
title = "Testosterone-mediated activation of androgenic signalling sustains in vitro the transformed and radioresistant phenotype of rhabdomyosarcoma cell lines",
abstract = "PURPOSE: Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in childhood, rarely affects adults, preferring male. RMS expresses the receptor for androgen (AR) and responds to androgen; however, the molecular action of androgens on RMS is unknown.METHODS: Herein, testosterone (T) effects were tested in embryonal (ERMS) and alveolar (ARMS) RMS cell lines, by performing luciferase reporter assay, RT-PCR, and western blotting experiments. RNA interference experiments or bicalutamide treatment was performed to assess the specific role of AR. Radiation treatment was delivered to characterise the effects of T treatment on RMS intrinsic radioresistance.RESULTS: Our study showed that RMS cells respond to sub-physiological levels of T stimulation, finally promoting AR-dependent genomic and non-genomic effects, such as the transcriptional regulation of several oncogenes, the phosphorylation-mediated post-transductional modifications of AR and the activation of ERK, p38 and AKT signal transduction pathway mediators that, by physically complexing or not with AR, participate in regulating its transcriptional activity and the expression of T-targeted genes. T chronic daily treatment, performed as for the hormone circadian rhythm, did not significantly affect RMS cell growth, but improved RMS clonogenic and radioresistant potential and increased AR mRNA both in ERMS and ARMS. AR protein accumulation was evident in ERMS, this further developing an intrinsic T-independent AR activity.CONCLUSIONS: Our results suggest that androgens sustain and improve RMS transformed and radioresistant phenotype, and therefore, their therapeutic application should be avoided in RMS post puberal patients.",
author = "S Giannattasio and F Megiorni and {Di Nisio}, V and {Del Fattore}, A and R Fontanella and S Camero and C Antinozzi and C Festuccia and Gravina, {G L} and S Cecconi and C Dominici and {Di Luigi}, L and C Ciccarelli and {De Cesaris}, P and A Riccioli and Zani, {B M} and A Lenzi and Pestell, {R G} and A Filippini and C Crescioli and V Tombolini and F Marampon",
year = "2018",
month = "5",
day = "22",
doi = "10.1007/s40618-018-0900-6",
language = "English",
journal = "Journal of Endocrinological Investigation",
issn = "0391-4097",
publisher = "Springer International Publishing",

}

TY - JOUR

T1 - Testosterone-mediated activation of androgenic signalling sustains in vitro the transformed and radioresistant phenotype of rhabdomyosarcoma cell lines

AU - Giannattasio, S

AU - Megiorni, F

AU - Di Nisio, V

AU - Del Fattore, A

AU - Fontanella, R

AU - Camero, S

AU - Antinozzi, C

AU - Festuccia, C

AU - Gravina, G L

AU - Cecconi, S

AU - Dominici, C

AU - Di Luigi, L

AU - Ciccarelli, C

AU - De Cesaris, P

AU - Riccioli, A

AU - Zani, B M

AU - Lenzi, A

AU - Pestell, R G

AU - Filippini, A

AU - Crescioli, C

AU - Tombolini, V

AU - Marampon, F

PY - 2018/5/22

Y1 - 2018/5/22

N2 - PURPOSE: Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in childhood, rarely affects adults, preferring male. RMS expresses the receptor for androgen (AR) and responds to androgen; however, the molecular action of androgens on RMS is unknown.METHODS: Herein, testosterone (T) effects were tested in embryonal (ERMS) and alveolar (ARMS) RMS cell lines, by performing luciferase reporter assay, RT-PCR, and western blotting experiments. RNA interference experiments or bicalutamide treatment was performed to assess the specific role of AR. Radiation treatment was delivered to characterise the effects of T treatment on RMS intrinsic radioresistance.RESULTS: Our study showed that RMS cells respond to sub-physiological levels of T stimulation, finally promoting AR-dependent genomic and non-genomic effects, such as the transcriptional regulation of several oncogenes, the phosphorylation-mediated post-transductional modifications of AR and the activation of ERK, p38 and AKT signal transduction pathway mediators that, by physically complexing or not with AR, participate in regulating its transcriptional activity and the expression of T-targeted genes. T chronic daily treatment, performed as for the hormone circadian rhythm, did not significantly affect RMS cell growth, but improved RMS clonogenic and radioresistant potential and increased AR mRNA both in ERMS and ARMS. AR protein accumulation was evident in ERMS, this further developing an intrinsic T-independent AR activity.CONCLUSIONS: Our results suggest that androgens sustain and improve RMS transformed and radioresistant phenotype, and therefore, their therapeutic application should be avoided in RMS post puberal patients.

AB - PURPOSE: Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in childhood, rarely affects adults, preferring male. RMS expresses the receptor for androgen (AR) and responds to androgen; however, the molecular action of androgens on RMS is unknown.METHODS: Herein, testosterone (T) effects were tested in embryonal (ERMS) and alveolar (ARMS) RMS cell lines, by performing luciferase reporter assay, RT-PCR, and western blotting experiments. RNA interference experiments or bicalutamide treatment was performed to assess the specific role of AR. Radiation treatment was delivered to characterise the effects of T treatment on RMS intrinsic radioresistance.RESULTS: Our study showed that RMS cells respond to sub-physiological levels of T stimulation, finally promoting AR-dependent genomic and non-genomic effects, such as the transcriptional regulation of several oncogenes, the phosphorylation-mediated post-transductional modifications of AR and the activation of ERK, p38 and AKT signal transduction pathway mediators that, by physically complexing or not with AR, participate in regulating its transcriptional activity and the expression of T-targeted genes. T chronic daily treatment, performed as for the hormone circadian rhythm, did not significantly affect RMS cell growth, but improved RMS clonogenic and radioresistant potential and increased AR mRNA both in ERMS and ARMS. AR protein accumulation was evident in ERMS, this further developing an intrinsic T-independent AR activity.CONCLUSIONS: Our results suggest that androgens sustain and improve RMS transformed and radioresistant phenotype, and therefore, their therapeutic application should be avoided in RMS post puberal patients.

U2 - 10.1007/s40618-018-0900-6

DO - 10.1007/s40618-018-0900-6

M3 - Article

C2 - 29790086

JO - Journal of Endocrinological Investigation

JF - Journal of Endocrinological Investigation

SN - 0391-4097

ER -