The androgen receptor is a negative regulator of eIF4E phosphorylation at S209: Implications for the use of mTOR inhibitors in advanced prostate cancer

L. S. D'Abronzo, S. Bose, M. E. Crapuchettes, R. E. Beggs, Ruth Louise Vinall, Clifford G Tepper, S. Siddiqui, Maria Mudryj, F. U. Melgoza, B. P. Durbin-Johnson, Ralph W deVere White, Paramita M Ghosh

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The antiandrogen bicalutamide is widely used in the treatment of advanced prostate cancer (PCa) in many countries, but its effect on castration-resistant PCa (CRPC) is limited. We previously showed that resistance to bicalutamide results from activation of mechanistic target of rapamycin (mTOR). Interestingly, clinical trials testing combinations of the mTOR inhibitor RAD001 with bicalutamide were effective in bicalutamide-naïve CRPC patients, but not in bicalutamide-pretreated ones. Here we investigate causes for their difference in response. Evaluation of CRPC cell lines identified resistant vs sensitive in vitro models, and revealed that increased eIF4E(S209) phosphorylation is associated with resistance to the combination. We confirmed using a human-derived tumor xenograft mouse model that bicalutamide pre-treatment is associated with an increase in eIF4E(S209) phosphorylation. Thus, AR suppressed eukaryotic initiation factor 4E (eIF4E) phosphorylation, while the use of antiandrogens relieved this suppression, thereby triggering its increase. Additional investigation in human prostatectomy samples showed that increased eIF4E phosphorylation strongly correlated with the cell proliferation marker Ki67. Small interfering RNA-mediated knockdown (k/d) of eIF4E-sensitized CRPC cells to RAD001+bicalutamide, whereas eIF4E overexpression induced resistance. Inhibition of eIF4E phosphorylation by treatment with CGP57380 (an inhibitor of mitogen-activated protein kinase-interacting serine-threonine kinases MAP kinase-interacting kinase 1 (Mnk1/2), the eIF4E upstream kinase) or inhibitors of extracellular signal-regulated kinase 1/2 (ERK1/2), the upstream kinase-regulating Mnk1/2, also sensitized CRPC cells to RAD001+bicalutamide. Examination of downstream targets of eIF4E-mediated translation, including survivin, demonstrated that eIF4E(S209) phosphorylation increased cap-independent translation, whereas its inhibition restored cap-dependent translation, which could be inhibited by mTOR inhibitors. Thus, our results demonstrate that while combinations of AR and mTOR inhibitors were effective in suppressing tumor growth by inhibiting both AR-induced transcription and mTOR-induced cap-dependent translation, pre-treatment with AR antagonists including bicalutamide increased eIF4E phosphorylation that induced resistance to combinations of AR and mTOR inhibitors by inducing cap-independent translation. We conclude that this resistance can be overcome by inhibiting eIF4E phosphorylation with Mnk1/2 or ERK1/2 inhibitors.

Original languageEnglish (US)
Pages (from-to)6359-6373
Number of pages15
JournalOncogene
Volume36
Issue number46
DOIs
StatePublished - Nov 16 2017

Fingerprint

Eukaryotic Initiation Factor-4E
Androgen Receptors
Sirolimus
Prostatic Neoplasms
Phosphorylation
Castration
Androgen Antagonists
Mitogen-Activated Protein Kinase 3
Protein-Serine-Threonine Kinases
Mitogen-Activated Protein Kinase 1
MAP Kinase Kinase Kinase 1
Phosphotransferases
bicalutamide
Prostatectomy
Mitogen-Activated Protein Kinases
Heterografts
Small Interfering RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

The androgen receptor is a negative regulator of eIF4E phosphorylation at S209 : Implications for the use of mTOR inhibitors in advanced prostate cancer. / D'Abronzo, L. S.; Bose, S.; Crapuchettes, M. E.; Beggs, R. E.; Vinall, Ruth Louise; Tepper, Clifford G; Siddiqui, S.; Mudryj, Maria; Melgoza, F. U.; Durbin-Johnson, B. P.; deVere White, Ralph W; Ghosh, Paramita M.

In: Oncogene, Vol. 36, No. 46, 16.11.2017, p. 6359-6373.

Research output: Contribution to journalArticle

D'Abronzo, LS, Bose, S, Crapuchettes, ME, Beggs, RE, Vinall, RL, Tepper, CG, Siddiqui, S, Mudryj, M, Melgoza, FU, Durbin-Johnson, BP, deVere White, RW & Ghosh, PM 2017, 'The androgen receptor is a negative regulator of eIF4E phosphorylation at S209: Implications for the use of mTOR inhibitors in advanced prostate cancer', Oncogene, vol. 36, no. 46, pp. 6359-6373. https://doi.org/10.1038/onc.2017.233
D'Abronzo, L. S. ; Bose, S. ; Crapuchettes, M. E. ; Beggs, R. E. ; Vinall, Ruth Louise ; Tepper, Clifford G ; Siddiqui, S. ; Mudryj, Maria ; Melgoza, F. U. ; Durbin-Johnson, B. P. ; deVere White, Ralph W ; Ghosh, Paramita M. / The androgen receptor is a negative regulator of eIF4E phosphorylation at S209 : Implications for the use of mTOR inhibitors in advanced prostate cancer. In: Oncogene. 2017 ; Vol. 36, No. 46. pp. 6359-6373.
@article{470c0b4a3f2746d7aaedda5fe277c2ce,
title = "The androgen receptor is a negative regulator of eIF4E phosphorylation at S209: Implications for the use of mTOR inhibitors in advanced prostate cancer",
abstract = "The antiandrogen bicalutamide is widely used in the treatment of advanced prostate cancer (PCa) in many countries, but its effect on castration-resistant PCa (CRPC) is limited. We previously showed that resistance to bicalutamide results from activation of mechanistic target of rapamycin (mTOR). Interestingly, clinical trials testing combinations of the mTOR inhibitor RAD001 with bicalutamide were effective in bicalutamide-na{\"i}ve CRPC patients, but not in bicalutamide-pretreated ones. Here we investigate causes for their difference in response. Evaluation of CRPC cell lines identified resistant vs sensitive in vitro models, and revealed that increased eIF4E(S209) phosphorylation is associated with resistance to the combination. We confirmed using a human-derived tumor xenograft mouse model that bicalutamide pre-treatment is associated with an increase in eIF4E(S209) phosphorylation. Thus, AR suppressed eukaryotic initiation factor 4E (eIF4E) phosphorylation, while the use of antiandrogens relieved this suppression, thereby triggering its increase. Additional investigation in human prostatectomy samples showed that increased eIF4E phosphorylation strongly correlated with the cell proliferation marker Ki67. Small interfering RNA-mediated knockdown (k/d) of eIF4E-sensitized CRPC cells to RAD001+bicalutamide, whereas eIF4E overexpression induced resistance. Inhibition of eIF4E phosphorylation by treatment with CGP57380 (an inhibitor of mitogen-activated protein kinase-interacting serine-threonine kinases MAP kinase-interacting kinase 1 (Mnk1/2), the eIF4E upstream kinase) or inhibitors of extracellular signal-regulated kinase 1/2 (ERK1/2), the upstream kinase-regulating Mnk1/2, also sensitized CRPC cells to RAD001+bicalutamide. Examination of downstream targets of eIF4E-mediated translation, including survivin, demonstrated that eIF4E(S209) phosphorylation increased cap-independent translation, whereas its inhibition restored cap-dependent translation, which could be inhibited by mTOR inhibitors. Thus, our results demonstrate that while combinations of AR and mTOR inhibitors were effective in suppressing tumor growth by inhibiting both AR-induced transcription and mTOR-induced cap-dependent translation, pre-treatment with AR antagonists including bicalutamide increased eIF4E phosphorylation that induced resistance to combinations of AR and mTOR inhibitors by inducing cap-independent translation. We conclude that this resistance can be overcome by inhibiting eIF4E phosphorylation with Mnk1/2 or ERK1/2 inhibitors.",
author = "D'Abronzo, {L. S.} and S. Bose and Crapuchettes, {M. E.} and Beggs, {R. E.} and Vinall, {Ruth Louise} and Tepper, {Clifford G} and S. Siddiqui and Maria Mudryj and Melgoza, {F. U.} and Durbin-Johnson, {B. P.} and {deVere White}, {Ralph W} and Ghosh, {Paramita M}",
year = "2017",
month = "11",
day = "16",
doi = "10.1038/onc.2017.233",
language = "English (US)",
volume = "36",
pages = "6359--6373",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "46",

}

TY - JOUR

T1 - The androgen receptor is a negative regulator of eIF4E phosphorylation at S209

T2 - Implications for the use of mTOR inhibitors in advanced prostate cancer

AU - D'Abronzo, L. S.

AU - Bose, S.

AU - Crapuchettes, M. E.

AU - Beggs, R. E.

AU - Vinall, Ruth Louise

AU - Tepper, Clifford G

AU - Siddiqui, S.

AU - Mudryj, Maria

AU - Melgoza, F. U.

AU - Durbin-Johnson, B. P.

AU - deVere White, Ralph W

AU - Ghosh, Paramita M

PY - 2017/11/16

Y1 - 2017/11/16

N2 - The antiandrogen bicalutamide is widely used in the treatment of advanced prostate cancer (PCa) in many countries, but its effect on castration-resistant PCa (CRPC) is limited. We previously showed that resistance to bicalutamide results from activation of mechanistic target of rapamycin (mTOR). Interestingly, clinical trials testing combinations of the mTOR inhibitor RAD001 with bicalutamide were effective in bicalutamide-naïve CRPC patients, but not in bicalutamide-pretreated ones. Here we investigate causes for their difference in response. Evaluation of CRPC cell lines identified resistant vs sensitive in vitro models, and revealed that increased eIF4E(S209) phosphorylation is associated with resistance to the combination. We confirmed using a human-derived tumor xenograft mouse model that bicalutamide pre-treatment is associated with an increase in eIF4E(S209) phosphorylation. Thus, AR suppressed eukaryotic initiation factor 4E (eIF4E) phosphorylation, while the use of antiandrogens relieved this suppression, thereby triggering its increase. Additional investigation in human prostatectomy samples showed that increased eIF4E phosphorylation strongly correlated with the cell proliferation marker Ki67. Small interfering RNA-mediated knockdown (k/d) of eIF4E-sensitized CRPC cells to RAD001+bicalutamide, whereas eIF4E overexpression induced resistance. Inhibition of eIF4E phosphorylation by treatment with CGP57380 (an inhibitor of mitogen-activated protein kinase-interacting serine-threonine kinases MAP kinase-interacting kinase 1 (Mnk1/2), the eIF4E upstream kinase) or inhibitors of extracellular signal-regulated kinase 1/2 (ERK1/2), the upstream kinase-regulating Mnk1/2, also sensitized CRPC cells to RAD001+bicalutamide. Examination of downstream targets of eIF4E-mediated translation, including survivin, demonstrated that eIF4E(S209) phosphorylation increased cap-independent translation, whereas its inhibition restored cap-dependent translation, which could be inhibited by mTOR inhibitors. Thus, our results demonstrate that while combinations of AR and mTOR inhibitors were effective in suppressing tumor growth by inhibiting both AR-induced transcription and mTOR-induced cap-dependent translation, pre-treatment with AR antagonists including bicalutamide increased eIF4E phosphorylation that induced resistance to combinations of AR and mTOR inhibitors by inducing cap-independent translation. We conclude that this resistance can be overcome by inhibiting eIF4E phosphorylation with Mnk1/2 or ERK1/2 inhibitors.

AB - The antiandrogen bicalutamide is widely used in the treatment of advanced prostate cancer (PCa) in many countries, but its effect on castration-resistant PCa (CRPC) is limited. We previously showed that resistance to bicalutamide results from activation of mechanistic target of rapamycin (mTOR). Interestingly, clinical trials testing combinations of the mTOR inhibitor RAD001 with bicalutamide were effective in bicalutamide-naïve CRPC patients, but not in bicalutamide-pretreated ones. Here we investigate causes for their difference in response. Evaluation of CRPC cell lines identified resistant vs sensitive in vitro models, and revealed that increased eIF4E(S209) phosphorylation is associated with resistance to the combination. We confirmed using a human-derived tumor xenograft mouse model that bicalutamide pre-treatment is associated with an increase in eIF4E(S209) phosphorylation. Thus, AR suppressed eukaryotic initiation factor 4E (eIF4E) phosphorylation, while the use of antiandrogens relieved this suppression, thereby triggering its increase. Additional investigation in human prostatectomy samples showed that increased eIF4E phosphorylation strongly correlated with the cell proliferation marker Ki67. Small interfering RNA-mediated knockdown (k/d) of eIF4E-sensitized CRPC cells to RAD001+bicalutamide, whereas eIF4E overexpression induced resistance. Inhibition of eIF4E phosphorylation by treatment with CGP57380 (an inhibitor of mitogen-activated protein kinase-interacting serine-threonine kinases MAP kinase-interacting kinase 1 (Mnk1/2), the eIF4E upstream kinase) or inhibitors of extracellular signal-regulated kinase 1/2 (ERK1/2), the upstream kinase-regulating Mnk1/2, also sensitized CRPC cells to RAD001+bicalutamide. Examination of downstream targets of eIF4E-mediated translation, including survivin, demonstrated that eIF4E(S209) phosphorylation increased cap-independent translation, whereas its inhibition restored cap-dependent translation, which could be inhibited by mTOR inhibitors. Thus, our results demonstrate that while combinations of AR and mTOR inhibitors were effective in suppressing tumor growth by inhibiting both AR-induced transcription and mTOR-induced cap-dependent translation, pre-treatment with AR antagonists including bicalutamide increased eIF4E phosphorylation that induced resistance to combinations of AR and mTOR inhibitors by inducing cap-independent translation. We conclude that this resistance can be overcome by inhibiting eIF4E phosphorylation with Mnk1/2 or ERK1/2 inhibitors.

UR - http://www.scopus.com/inward/record.url?scp=85034435359&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85034435359&partnerID=8YFLogxK

U2 - 10.1038/onc.2017.233

DO - 10.1038/onc.2017.233

M3 - Article

C2 - 28745319

AN - SCOPUS:85034435359

VL - 36

SP - 6359

EP - 6373

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 46

ER -