Inhibition of the phosphatidylinositol 3'-kinase pathway promotes autocrine fas-induced death of phosphatase and tensin homologue-deficient prostate cancer cells
Rationally designed therapeutics that target the phosphatidylinositol 3'-kinase (PI3K) cell survival pathway are currently in preclinical and clinical development for cancer therapy. Drugs targeting the PI3K pathway aim to inhibit proliferation, promote apoptosis, and enhance chemosensitivity a...
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Published in | Cancer research (Chicago, Ill.) Vol. 66; no. 9; pp. 4781 - 4788 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
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Philadelphia, PA
American Association for Cancer Research
01.05.2006
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Abstract | Rationally designed therapeutics that target the phosphatidylinositol 3'-kinase (PI3K) cell survival pathway are currently in preclinical and clinical development for cancer therapy. Drugs targeting the PI3K pathway aim to inhibit proliferation, promote apoptosis, and enhance chemosensitivity and radiosensitivity of cancer cells. The phosphatase and tensin homologue (PTEN) phosphatidylinositol 3'-phosphatase is a key negative regulator of the PI3K pathway. Inactivation of the PTEN tumor suppressor results in constitutive activation of the PI3K pathway and is found in approximately 50% of advanced prostate cancers, which correlates with a high Gleason score and poor prognosis. Inhibition of the PI3K pathway leads to apoptosis of prostate cancer cells; however, the precise mechanism by which this occurs is unknown. Here we report that apoptotic cell death of PTEN-deficient LNCaP and PC3 prostate cancer cells induced by the PI3K inhibitor LY294002 can be abrogated by disrupting Fas/Fas ligand (FasL) interactions with recombinant Fas:Fc fusion protein or FasL neutralizing antibody (Nok-1), or by expressing dominant-negative Fas-associated death domain. Furthermore, we find that apoptosis induced by expression of wild-type PTEN, driven by a tetracycline-inducible expression system in LNCaP cells, can be inhibited by blocking Fas/FasL interaction using Fas:Fc or Nok-1. These data show that apoptosis induced by blockade of the PI3K pathway in prostate tumor cells is mediated by an autocrine Fas/FasL apoptotic mechanism and the Fas apoptotic pathway is both necessary and sufficient to mediate apoptosis by PI3K inhibition. |
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AbstractList | Abstract
Rationally designed therapeutics that target the phosphatidylinositol 3′-kinase (PI3K) cell survival pathway are currently in preclinical and clinical development for cancer therapy. Drugs targeting the PI3K pathway aim to inhibit proliferation, promote apoptosis, and enhance chemosensitivity and radiosensitivity of cancer cells. The phosphatase and tensin homologue (PTEN) phosphatidylinositol 3′-phosphatase is a key negative regulator of the PI3K pathway. Inactivation of the PTEN tumor suppressor results in constitutive activation of the PI3K pathway and is found in ∼50% of advanced prostate cancers, which correlates with a high Gleason score and poor prognosis. Inhibition of the PI3K pathway leads to apoptosis of prostate cancer cells; however, the precise mechanism by which this occurs is unknown. Here we report that apoptotic cell death of PTEN-deficient LNCaP and PC3 prostate cancer cells induced by the PI3K inhibitor LY294002 can be abrogated by disrupting Fas/Fas ligand (FasL) interactions with recombinant Fas:Fc fusion protein or FasL neutralizing antibody (Nok-1), or by expressing dominant-negative Fas-associated death domain. Furthermore, we find that apoptosis induced by expression of wild-type PTEN, driven by a tetracycline-inducible expression system in LNCaP cells, can be inhibited by blocking Fas/FasL interaction using Fas:Fc or Nok-1. These data show that apoptosis induced by blockade of the PI3K pathway in prostate tumor cells is mediated by an autocrine Fas/FasL apoptotic mechanism and the Fas apoptotic pathway is both necessary and sufficient to mediate apoptosis by PI3K inhibition. (Cancer Res 2006; 66(9): 4781-8) Rationally designed therapeutics that target the phosphatidylinositol 3'-kinase (PI3K) cell survival pathway are currently in preclinical and clinical development for cancer therapy. Drugs targeting the PI3K pathway aim to inhibit proliferation, promote apoptosis, and enhance chemosensitivity and radiosensitivity of cancer cells. The phosphatase and tensin homologue (PTEN) phosphatidylinositol 3'-phosphatase is a key negative regulator of the PI3K pathway. Inactivation of the PTEN tumor suppressor results in constitutive activation of the PI3K pathway and is found in approximately 50% of advanced prostate cancers, which correlates with a high Gleason score and poor prognosis. Inhibition of the PI3K pathway leads to apoptosis of prostate cancer cells; however, the precise mechanism by which this occurs is unknown. Here we report that apoptotic cell death of PTEN-deficient LNCaP and PC3 prostate cancer cells induced by the PI3K inhibitor LY294002 can be abrogated by disrupting Fas/Fas ligand (FasL) interactions with recombinant Fas:Fc fusion protein or FasL neutralizing antibody (Nok-1), or by expressing dominant-negative Fas-associated death domain. Furthermore, we find that apoptosis induced by expression of wild-type PTEN, driven by a tetracycline-inducible expression system in LNCaP cells, can be inhibited by blocking Fas/FasL interaction using Fas:Fc or Nok-1. These data show that apoptosis induced by blockade of the PI3K pathway in prostate tumor cells is mediated by an autocrine Fas/FasL apoptotic mechanism and the Fas apoptotic pathway is both necessary and sufficient to mediate apoptosis by PI3K inhibition. |
Author | GLEAVE, Martin E CHUNG, Stephen W TAN, Clara PEACOCK, James W MUI, Alice L-F COX, Michael E ONG, Christopher J DEDHAR, Shoukat BERTRAM, Jerod |
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Keywords | Urinary system disease Prostate disease Enzyme Transferases Mortality Phosphoric monoester hydrolases Homology Esterases Malignant tumor Autocrine regulation 1-Phosphatidylinositol 3-kinase Fas Antigen Hydrolases Death Inhibitor Male genital diseases Prostate cancer Tumor cell |
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Snippet | Rationally designed therapeutics that target the phosphatidylinositol 3'-kinase (PI3K) cell survival pathway are currently in preclinical and clinical... Abstract Rationally designed therapeutics that target the phosphatidylinositol 3′-kinase (PI3K) cell survival pathway are currently in preclinical and clinical... |
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SubjectTerms | Adaptor Proteins, Signal Transducing - metabolism Antibodies - immunology Antibodies - pharmacology Antineoplastic agents Apoptosis - drug effects Apoptosis - physiology Biological and medical sciences Cell Line, Tumor Chromones - pharmacology Enzyme Inhibitors - pharmacology Fas Ligand Protein fas Receptor - biosynthesis fas Receptor - genetics fas Receptor - metabolism fas Receptor - pharmacology Fas-Associated Death Domain Protein Gynecology. Andrology. Obstetrics Humans Male Male genital diseases Medical sciences Membrane Glycoproteins - antagonists & inhibitors Membrane Glycoproteins - biosynthesis Membrane Glycoproteins - immunology Membrane Glycoproteins - metabolism Morpholines - pharmacology Nephrology. Urinary tract diseases Pharmacology. Drug treatments Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - metabolism Prostatic Neoplasms - drug therapy Prostatic Neoplasms - enzymology Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology PTEN Phosphohydrolase - biosynthesis PTEN Phosphohydrolase - deficiency PTEN Phosphohydrolase - genetics Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - pharmacology Signal Transduction - drug effects Transfection Tumor Necrosis Factors - antagonists & inhibitors Tumor Necrosis Factors - biosynthesis Tumor Necrosis Factors - immunology Tumor Necrosis Factors - metabolism Tumors Tumors of the urinary system Urinary tract. Prostate gland |
Title | Inhibition of the phosphatidylinositol 3'-kinase pathway promotes autocrine fas-induced death of phosphatase and tensin homologue-deficient prostate cancer cells |
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