Remarkable inhibition of mTOR signaling by the combination of rapamycin and 1,4-phenylenebis(methylene)selenocyanate in human prostate cancer cells

Nicole D. Facompre, Indu Sinha, Karam El-Bayoumy, John T. Pinto, Raghu Sinha

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Abstract

Preclinical studies and clinical analyses have implicated the mammalian target of rapamycin (mTOR) pathway in the progression of prostate cancer, suggesting mTOR as a potential target for new therapies. mTOR, a serine/threonine kinase, belongs to two distinct signaling complexes: mTORC1 and mTORC2. We previously showed that the synthetic organoselenium compound, p-XSC, effectively inhibits viability and critical signaling molecules (e.g., androgen receptor, Akt) in androgen responsive (AR) and androgen independent (AI) human prostate cancer cells. On the basis of its inhibition of Akt, we hypothesized that p-XSC modulates mTORC2, an upstream regulator of the kinase. We further hypothesized that combining p-XSC with rapamycin, an mTORC1 inhibitor, would be an effective combinatory strategy for the inhibition of prostate cancer. The effects of p-XSC and rapamycin, alone or in combination, on viability and mTOR signaling were examined in AR LNCaP prostate cancer cells and AI C4-2 and DU145 cells. Phosphorylation of downstream targets of mTORC1 and mTORC2 was analyzed by immunoblotting. The interaction of mTORC1- and mTORC2-specific proteins with mTOR was probed through immunoprecipitation and immunoblotting. p-XSC inhibited phosphorylation of mTORC2 downstream targets, Akt and PCKα, and decreased the levels of rictor, an mTORC2-specific protein, coimmunoprecipitated with mTOR in C4-2 cells. The combination of p-XSC and rapamycin more effectively inhibited viability and mTOR signaling in C4-2, LNCaP and DU145 cells than either agent individually.

Original languageEnglish (US)
Pages (from-to)2134-2142
Number of pages9
JournalInternational Journal of Cancer
Volume131
Issue number9
DOIs
StatePublished - Nov 1 2012

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Sirolimus
Prostatic Neoplasms
Androgens
Immunoblotting
Organoselenium Compounds
Phosphorylation
1,4-phenylenebis(methylene)selenocyanate
Protein-Serine-Threonine Kinases
Androgen Receptors
Immunoprecipitation
TOR complex 2
Proteins
Phosphotransferases
mechanistic target of rapamycin complex 1

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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title = "Remarkable inhibition of mTOR signaling by the combination of rapamycin and 1,4-phenylenebis(methylene)selenocyanate in human prostate cancer cells",
abstract = "Preclinical studies and clinical analyses have implicated the mammalian target of rapamycin (mTOR) pathway in the progression of prostate cancer, suggesting mTOR as a potential target for new therapies. mTOR, a serine/threonine kinase, belongs to two distinct signaling complexes: mTORC1 and mTORC2. We previously showed that the synthetic organoselenium compound, p-XSC, effectively inhibits viability and critical signaling molecules (e.g., androgen receptor, Akt) in androgen responsive (AR) and androgen independent (AI) human prostate cancer cells. On the basis of its inhibition of Akt, we hypothesized that p-XSC modulates mTORC2, an upstream regulator of the kinase. We further hypothesized that combining p-XSC with rapamycin, an mTORC1 inhibitor, would be an effective combinatory strategy for the inhibition of prostate cancer. The effects of p-XSC and rapamycin, alone or in combination, on viability and mTOR signaling were examined in AR LNCaP prostate cancer cells and AI C4-2 and DU145 cells. Phosphorylation of downstream targets of mTORC1 and mTORC2 was analyzed by immunoblotting. The interaction of mTORC1- and mTORC2-specific proteins with mTOR was probed through immunoprecipitation and immunoblotting. p-XSC inhibited phosphorylation of mTORC2 downstream targets, Akt and PCKα, and decreased the levels of rictor, an mTORC2-specific protein, coimmunoprecipitated with mTOR in C4-2 cells. The combination of p-XSC and rapamycin more effectively inhibited viability and mTOR signaling in C4-2, LNCaP and DU145 cells than either agent individually.",
author = "Facompre, {Nicole D.} and Indu Sinha and Karam El-Bayoumy and Pinto, {John T.} and Raghu Sinha",
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T1 - Remarkable inhibition of mTOR signaling by the combination of rapamycin and 1,4-phenylenebis(methylene)selenocyanate in human prostate cancer cells

AU - Facompre, Nicole D.

AU - Sinha, Indu

AU - El-Bayoumy, Karam

AU - Pinto, John T.

AU - Sinha, Raghu

PY - 2012/11/1

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N2 - Preclinical studies and clinical analyses have implicated the mammalian target of rapamycin (mTOR) pathway in the progression of prostate cancer, suggesting mTOR as a potential target for new therapies. mTOR, a serine/threonine kinase, belongs to two distinct signaling complexes: mTORC1 and mTORC2. We previously showed that the synthetic organoselenium compound, p-XSC, effectively inhibits viability and critical signaling molecules (e.g., androgen receptor, Akt) in androgen responsive (AR) and androgen independent (AI) human prostate cancer cells. On the basis of its inhibition of Akt, we hypothesized that p-XSC modulates mTORC2, an upstream regulator of the kinase. We further hypothesized that combining p-XSC with rapamycin, an mTORC1 inhibitor, would be an effective combinatory strategy for the inhibition of prostate cancer. The effects of p-XSC and rapamycin, alone or in combination, on viability and mTOR signaling were examined in AR LNCaP prostate cancer cells and AI C4-2 and DU145 cells. Phosphorylation of downstream targets of mTORC1 and mTORC2 was analyzed by immunoblotting. The interaction of mTORC1- and mTORC2-specific proteins with mTOR was probed through immunoprecipitation and immunoblotting. p-XSC inhibited phosphorylation of mTORC2 downstream targets, Akt and PCKα, and decreased the levels of rictor, an mTORC2-specific protein, coimmunoprecipitated with mTOR in C4-2 cells. The combination of p-XSC and rapamycin more effectively inhibited viability and mTOR signaling in C4-2, LNCaP and DU145 cells than either agent individually.

AB - Preclinical studies and clinical analyses have implicated the mammalian target of rapamycin (mTOR) pathway in the progression of prostate cancer, suggesting mTOR as a potential target for new therapies. mTOR, a serine/threonine kinase, belongs to two distinct signaling complexes: mTORC1 and mTORC2. We previously showed that the synthetic organoselenium compound, p-XSC, effectively inhibits viability and critical signaling molecules (e.g., androgen receptor, Akt) in androgen responsive (AR) and androgen independent (AI) human prostate cancer cells. On the basis of its inhibition of Akt, we hypothesized that p-XSC modulates mTORC2, an upstream regulator of the kinase. We further hypothesized that combining p-XSC with rapamycin, an mTORC1 inhibitor, would be an effective combinatory strategy for the inhibition of prostate cancer. The effects of p-XSC and rapamycin, alone or in combination, on viability and mTOR signaling were examined in AR LNCaP prostate cancer cells and AI C4-2 and DU145 cells. Phosphorylation of downstream targets of mTORC1 and mTORC2 was analyzed by immunoblotting. The interaction of mTORC1- and mTORC2-specific proteins with mTOR was probed through immunoprecipitation and immunoblotting. p-XSC inhibited phosphorylation of mTORC2 downstream targets, Akt and PCKα, and decreased the levels of rictor, an mTORC2-specific protein, coimmunoprecipitated with mTOR in C4-2 cells. The combination of p-XSC and rapamycin more effectively inhibited viability and mTOR signaling in C4-2, LNCaP and DU145 cells than either agent individually.

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