hPEBP4 Resists TRAIL-induced Apoptosis of Human Prostate Cancer Cells by Activating Akt and Deactivating ERK1/2 Pathways

Abstract

The treatment options available for prostate cancer are limited because of its resistance to therapeutic agents. Thus, a better understanding of the underlying mechanisms of the resistance of prostate cancer will facilitate the discovery of more efficient treatment protocols. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is recently identified by us as an anti-apoptotic molecule and a potential candidate target for breast cancer treatment. Here we found the expression levels of hPEBP4 were positively correlated with the severity of clinical prostate cancer. Furthermore, hPEBP4 was not expressed in TRAIL-sensitive DU145 prostate cancer cells, but was highly expressed in TRAIL-resistant LNCaP cells, which show highly activated Akt. Interestingly, hPEBP4 overexpression in TRAIL-sensitive DU145 cells promoted Akt but The DU145 cells to which by of hPEBP4 in TRAIL-resistant LNCaP cells Akt but in to was by the hPEBP4 expression in prostate cancer Akt and to resistance to of and the of the of Akt and and was of Akt in prostate cancer hPEBP4 resistance to and is expressed in prostate of hPEBP4 a for prostate cancer treatment. The treatment options available for prostate cancer are limited because of its resistance to therapeutic agents. Thus, a better understanding of the underlying mechanisms of the resistance of prostate cancer will facilitate the discovery of more efficient treatment protocols. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is recently identified by us as an anti-apoptotic molecule and a potential candidate target for breast cancer treatment. Here we found the expression levels of hPEBP4 were positively correlated with the severity of clinical prostate cancer. Furthermore, hPEBP4 was not expressed in TRAIL-sensitive DU145 prostate cancer cells, but was highly expressed in TRAIL-resistant LNCaP cells, which show highly activated Akt. Interestingly, hPEBP4 overexpression in TRAIL-sensitive DU145 cells promoted Akt but The DU145 cells to which by of hPEBP4 in TRAIL-resistant LNCaP cells Akt but in to was by the hPEBP4 expression in prostate cancer Akt and to resistance to of and the of the of Akt and and was of Akt in prostate cancer hPEBP4 resistance to and is expressed in prostate of hPEBP4 a for prostate cancer treatment. cancer is the and of the of cancer in The of prostate cancer as a the as of to of and are not for prostate cancer a better understanding of mechanisms for the resistance of prostate cancer cells to therapeutic will to more efficient treatment protocols. the of prostate and the and are the protein phosphatidylethanolamine-binding protein protein phosphatidylethanolamine-binding protein and in and prostate and the of prostate cancer to an The of is in a in the of prostate cancer of Akt and of in prostate and Akt with is an of clinical in prostate cancer of the Akt is as of the for resistance of prostate cancer to therapeutic and to Akt in to the therapeutic of prostate the and which to the and of in a and in cells is in clinical as an for Akt and are of in prostate cancer Akt as and and and and the is for of prostate cancer cells to of Akt and the resistance of phosphatidylethanolamine-binding protein 4 (hPEBP4) is a of the identified by us as an anti-apoptotic molecule hPEBP4 is expressed in breast cancer and cancer cells of hPEBP4 in breast cancer cells and hPEBP4 is a candidate target molecule for breast cancer treatment hPEBP4 was highly expressed in prostate cancer the of is to the of hPEBP4 as a therapeutic target in prostate cancer. prostate cancer TRAIL-resistant LNCaP prostate cancer cells and TRAIL-sensitive DU145 cells as to the hPEBP4 expression and Interestingly, hPEBP4 was found to highly expressed in TRAIL-resistant LNCaP prostate cancer cells, but not in TRAIL-sensitive DU145 we found hPEBP4 expression is positively with the severity of prostate cancer. Furthermore, we hPEBP4 by Akt and and the of and the of of hPEBP4 a for the treatment of prostate and was was to and were and to and and were The and and the were prostate cancer cells were in with and in a of hPEBP4 in of prostate and prostate cancer were The in and was and as to to the of prostate a of of were available for with cancer. The were with in and with of and and the of were to by The is as cells of cells of cells and of cells and were the was as and the was was by with and in for and of expression hPEBP4 expression and were as and DU145 cells with as a the cells were for were as and The hPEBP4 expression was by and of hPEBP4 expression in prostate cancer LNCaP cells, the cells were with the as the cells were for were as and and hPEBP4 was by and were in the and with to the cells were by was to protein of protein were by and to were with the with as was for the of and DU145 cells were for with for and in The were with 4 and in and and was as of hPEBP4 LNCaP with LNCaP were with protein and to protein as hPEBP4 expression and of prostate cancer was with the of hPEBP4 in hPEBP4 was highly expressed in breast cancer and hPEBP4 was highly expressed in breast and prostate cancer the hPEBP4 expression and the of prostate we the expression of hPEBP4 in prostate cancer by hPEBP4 expression was to in a of prostate cancer with the in and in prostate The the expression of hPEBP4 in prostate cancer of hPEBP4 was with of of the of the and in of and of for hPEBP4 a of hPEBP4 expression with the severity of prostate cancer and hPEBP4 in the and of prostate cancer. The expression of hPEBP4 in prostate cancer was was found to not expressed in TRAIL-sensitive DU145 prostate cancer cells, but highly in TRAIL-resistant LNCaP cells hPEBP4 in the resistance of prostate cancer to hPEBP4 the severity of prostate and and and and in a hPEBP4 Akt and in Human is Akt and are in of prostate cancer cells, and Akt and clinical in prostate cancer hPEBP4 was expressed in prostate cancer cells, in LNCaP cells, which show levels of activated with of by the of hPEBP4 expression in prostate cancer cells the of Akt and was TRAIL-sensitive DU145 cells with expression of hPEBP4 were with hPEBP4 expression not and the overexpression of hPEBP4 in DU145 with of Akt not in levels but the of the was and TRAIL-resistant LNCaP cells with expression of hPEBP4 were with and the of hPEBP4 expression in LNCaP cells of hPEBP4 in LNCaP cells the levels of Akt and Akt but promoted and the of and the in was by hPEBP4 expression hPEBP4 Akt and in prostate cancer and in prostate cancer DU145 cells were with and expression of hPEBP4 was by with and of hPEBP4 overexpression Akt and of DU145 cells were for and with for protein of were with the of Akt and of hPEBP4 expression in LNCaP cells was by and with and hPEBP4 the and Akt and promoted of LNCaP cells were for and with for the hPEBP4 and in Akt and to prostate cancer cells of Akt by hPEBP4 with its highly expression in TRAIL-resistant prostate cancer cells, promoted us to the of hPEBP4 in the resistance of prostate cancer to in DU145 and cells were highly to the cells hPEBP4 were to hPEBP4 the resistance in prostate cancer. The of a of hPEBP4 the not DU145 cells to is the of hPEBP4 resistance in prostate cancer LNCaP cells to the of hPEBP4 resistance in prostate cancer Akt and DU145 cells were for and with and The cells are as the of of hPEBP4 the LNCaP cells to LNCaP cells were with for and with by the of hPEBP4 with in The of DU145 cells were with for with for in LNCaP with in were with for and with for was by hPEBP4 not the expression levels of and the resistance the Akt we the cells with for and the cells with Akt not and the of hPEBP4 in DU145 cells LNCaP cells we the to the by hPEBP4 LNCaP cells were with for and with in the of of LNCaP cells, of by hPEBP4 in LNCaP the protein expression of and in the LNCaP cells, and found the expression levels of the hPEBP4 by the expression of hPEBP4 resistance in prostate cancer cells by Akt and by of Akt and is is a hPEBP4 in prostate cancer cells, we the of and in DU145 with of hPEBP4 in DU145 cells the of but which by of prostate cancer cells of which in we the of hPEBP4 of hPEBP4 in DU145 cells which by resistance in DU145 cells of and the of overexpression of hPEBP4 of and in DU145 cells the protein of as and not and in of and Akt as a which found overexpression of hPEBP4 of the protein of with by the of hPEBP4 protein The hPEBP4 resistance by the expression of which of and the of and is for Akt the expression of and its for Akt and of DU145 cells were with for not and with for were to and with and which and its cells as in were to and with and of LNCaP cells were with for and with for were to and with the the of hPEBP4 expression in LNCaP cells of of of and of and the the hPEBP4 of protein expression by resistance by expression of for the Akt in Human hPEBP4 to the and to and in breast cancer cells we to hPEBP4 the to in DU145 cells and LNCaP The and were in the of DU145 cells and LNCaP cells with but not in of cells and the of hPEBP4 with Akt was not not is for the Akt in prostate cancer hPEBP4 with of DU145 cells with for not were with The were hPEBP4 protein in LNCaP cells with LNCaP were with for and with The of Akt and were by in DU145 The of hPEBP4 in DU145 cells were with and with for the the and to we the the of by hPEBP4 for the of Akt LNCaP cells were with to we found and the of Akt by hPEBP4 to the of Akt the in DU145 Interestingly, we found and the in to the Akt in prostate cancer understanding of the facilitate prostate cancer and mechanisms in the will to the of for the treatment of prostate cancer. therapeutic potential its to in cancer with not cancer cells with mechanisms to of the resistance are Akt and Akt was in more of of prostate and with prostate cancer levels of in Akt and in cancer cells, and highly activated Akt to correlated with and resistance to in prostate cancer of the of as Akt by a molecule an therapeutic for prostate cancer we by the of prostate cancer the severity of prostate cancer is with expression of which was recently identified as an molecule by us Furthermore, hPEBP4 was highly expressed in TRAIL-resistant LNCaP cells, which show highly levels of but not in TRAIL-sensitive DU145 is overexpression of hPEBP4 in DU145 cells promoted Akt but the DU145 cells to which by of hPEBP4 in TRAIL-resistant LNCaP cells the highly Akt but in to The resistance in LNCaP Thus, of and Akt to for the of the expression of hPEBP4 in prostate cancer to of Akt and of in of treatment for prostate cancer. The of hPEBP4 a for the treatment of levels of prostate cancer cells, which of a which is of and a and the hPEBP4 and but Thus, the of of the of hPEBP4 which by and hPEBP4 to and Here the hPEBP4 with and was in DU145 cells hPEBP4 LNCaP cells with hPEBP4 we not found the of hPEBP4 with Akt the and the of in the of as as the of in the Akt and the of Akt by hPEBP4 in LNCaP in DU145 we not of hPEBP4 and not the hPEBP4 promoted Akt in an will to the of Akt in prostate cancer the we the of resistance in prostate cancer hPEBP4 to and to the facilitate to with the Akt hPEBP4 Akt in Akt in the of and of to the of for the of hPEBP4 in the resistance of prostate cancer cells to hPEBP4 of the but Akt The activated Akt in of and of cancer is the and of the of cancer in The of prostate cancer as a the as of to of and are not for prostate cancer a better understanding of mechanisms for the resistance of prostate cancer cells to therapeutic will to more efficient treatment protocols. the of prostate and the and are the protein phosphatidylethanolamine-binding protein protein phosphatidylethanolamine-binding protein and in and prostate and the of prostate cancer to an The of is in a in the of prostate cancer of Akt and of in prostate and Akt with is an of clinical in prostate cancer of the Akt is as of the for resistance of prostate cancer to therapeutic and to Akt in to the therapeutic of prostate cancer. the and which to the and of in a and in cells is in clinical as an for Akt and are of in prostate cancer Akt as and and and and the is for of prostate cancer cells to of Akt and the resistance of Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is a of the identified by us as an anti-apoptotic molecule hPEBP4 is expressed in breast cancer and cancer cells of hPEBP4 in breast cancer cells and hPEBP4 is a candidate target molecule for breast cancer treatment hPEBP4 was highly expressed in prostate cancer the of is to the of hPEBP4 as a therapeutic target in prostate cancer. prostate cancer TRAIL-resistant LNCaP prostate cancer cells and TRAIL-sensitive DU145 cells as to the hPEBP4 expression and Interestingly, hPEBP4 was found to highly expressed in TRAIL-resistant LNCaP prostate cancer cells, but not in TRAIL-sensitive DU145 we found hPEBP4 expression is positively with the severity of prostate cancer. Furthermore, we hPEBP4 by Akt and and the of and the of of hPEBP4 a for the treatment of prostate cancer. and was was to and were and to and and were The and and the were prostate cancer cells were in with and in a of hPEBP4 in of prostate and prostate cancer were The in and was and as to to the of prostate a of of were available for with cancer. The were with in and with of and and the of were to by The is as cells of cells of cells and of cells and were the was as and the was was by with and in for and of expression hPEBP4 expression and were as and DU145 cells with as a the cells were for were as and The hPEBP4 expression was by and of hPEBP4 expression in prostate cancer LNCaP cells, the cells were with the as the cells were for were as and and hPEBP4 was by and were in the and with to the cells were by was to protein of protein were by and to were with the with as was for the of and DU145 cells were for with for and in The were with 4 and in and and was as of hPEBP4 LNCaP with LNCaP were with protein and to protein as hPEBP4 expression and of prostate cancer was with the and was was to and were and to and and were The and and the were prostate cancer cells were in with and in a of hPEBP4 in of prostate and prostate cancer were The in and was and as to to the of prostate a of of were available for with cancer. The were with in and with The of and and the of were to by The is as cells of cells of cells and of cells and were the was as and the was was by with and in for and of expression hPEBP4 expression and were as and DU145 cells with as a the cells were for were as and The hPEBP4 expression was by and hPEBP4 of hPEBP4 expression in prostate cancer LNCaP cells, the cells were with the as the cells were for were as and and hPEBP4 was by and were in the and with to the cells were by was to protein of protein were by and to were with the with as was for the of and DU145 cells were for with for and in The were with 4 and in and and was as of hPEBP4 LNCaP with LNCaP were with protein and to protein as hPEBP4 expression and of prostate cancer was with the of hPEBP4 in hPEBP4 was highly expressed in breast cancer and hPEBP4 was highly expressed in breast and prostate cancer the hPEBP4 expression and the of prostate we the expression of hPEBP4 in prostate cancer by hPEBP4 expression was to in a of prostate cancer with the in and in prostate The the expression of hPEBP4 in prostate cancer of hPEBP4 was with of of the of the and in of and of for hPEBP4 a of hPEBP4 expression with the severity of prostate cancer and hPEBP4 in the and of prostate cancer. The expression of hPEBP4 in prostate cancer was was found to not expressed in TRAIL-sensitive DU145 prostate cancer cells, but highly in TRAIL-resistant LNCaP cells hPEBP4 in the resistance of prostate cancer to hPEBP4 the severity of prostate and and and and in a hPEBP4 Akt and in Human is Akt and are in of prostate cancer cells, and Akt and clinical in prostate cancer hPEBP4 was expressed in prostate cancer cells, in LNCaP cells, which show levels of activated with of by the of hPEBP4 expression in prostate cancer cells the of Akt and was TRAIL-sensitive DU145 cells with expression of hPEBP4 were with hPEBP4 expression not and the overexpression of hPEBP4 in DU145 with of Akt not in levels but the of the was and TRAIL-resistant LNCaP cells with expression of hPEBP4 were with and the of hPEBP4 expression in LNCaP cells of hPEBP4 in LNCaP cells the levels of Akt and Akt but promoted and the of and the in was by hPEBP4 expression hPEBP4 Akt and in prostate cancer in Akt and to prostate cancer cells of Akt by hPEBP4 with its highly expression in TRAIL-resistant prostate cancer cells, promoted us to the of hPEBP4 in the resistance of prostate cancer to in DU145 and cells were highly to the cells hPEBP4 were to hPEBP4 the resistance in prostate cancer. The of a of hPEBP4 the not DU145 cells to is the of hPEBP4 resistance in prostate cancer LNCaP cells to the of hPEBP4 resistance in prostate cancer Akt and DU145 cells were for and with and The cells are as the of of hPEBP4 the LNCaP cells to LNCaP cells were with for and with by the of hPEBP4 with in The of DU145 cells were with for with for in LNCaP with in were with for and with for was by hPEBP4 not the expression levels of and the resistance the Akt we the cells with for and the cells with Akt not and the of hPEBP4 in DU145 cells LNCaP cells we the to the by hPEBP4 LNCaP cells were with for and with in the of of LNCaP cells, of by hPEBP4 in LNCaP the protein expression of and in the LNCaP cells, and found the expression levels of the hPEBP4 by the expression of hPEBP4 resistance in prostate cancer cells by Akt and by of Akt and is is a hPEBP4 in prostate cancer cells, we the of and in DU145 with of hPEBP4 in DU145 cells the of but which by of prostate cancer cells of which in we the of hPEBP4 of hPEBP4 in DU145 cells which by resistance in DU145 cells of and the of overexpression of hPEBP4 of and in DU145 cells the protein of as and not and in of and Akt as a which found overexpression of hPEBP4 of the protein of with by the of hPEBP4 protein The hPEBP4 resistance by the expression of which of and the of and is for Akt the expression of and its for Akt and of DU145 cells were with for not and with for were to and with and which and its cells as in were to and with and of LNCaP cells were with for and with for were to and with the the of hPEBP4 expression in LNCaP cells of of of and of and the the hPEBP4 of protein expression by resistance by expression of for the Akt in Human hPEBP4 to the and to and in breast cancer cells we to hPEBP4 the to in DU145 cells and LNCaP The and were in the of DU145 cells and LNCaP cells with but not in of cells and the of hPEBP4 with Akt was not not is for the Akt in prostate cancer hPEBP4 with of DU145 cells with for not were with The were hPEBP4 protein in LNCaP cells with LNCaP were with for and with The of Akt and were by in DU145 The of hPEBP4 in DU145 cells were with and with for the the and to we the the of by hPEBP4 for the of Akt LNCaP cells were with to we found and the of Akt by hPEBP4 to the of Akt the in DU145 Interestingly, we found and the in to the Akt in prostate cancer of hPEBP4 in hPEBP4 was highly expressed in breast cancer and hPEBP4 was highly expressed in breast and prostate cancer the hPEBP4 expression and the of prostate we the expression of hPEBP4 in prostate cancer by hPEBP4 expression was to in a of prostate cancer with the in and in prostate The the expression of hPEBP4 in prostate cancer of hPEBP4 was with of of the of the and in of and of for hPEBP4 a of hPEBP4 expression with the severity of prostate cancer and hPEBP4 in the and of prostate cancer. The expression of hPEBP4 in prostate cancer was was found to not expressed in TRAIL-sensitive DU145 prostate cancer cells, but highly in TRAIL-resistant LNCaP cells hPEBP4 in the resistance of prostate cancer to hPEBP4 Akt and in Human is Akt and are in of prostate cancer cells, and Akt and clinical in prostate cancer hPEBP4 was expressed in prostate cancer cells, in LNCaP cells, which show levels of activated with of by the of hPEBP4 expression in prostate cancer cells the of Akt and was TRAIL-sensitive DU145 cells with expression of hPEBP4 were with hPEBP4 expression not and the overexpression of hPEBP4 in DU145 with of Akt not in levels but the of the was and TRAIL-resistant LNCaP cells with expression of hPEBP4 were with and the of hPEBP4 expression in LNCaP cells of hPEBP4 in LNCaP cells the levels of Akt and Akt but promoted and the of and the in was by hPEBP4 expression hPEBP4 Akt and in prostate cancer hPEBP4 in Akt and to prostate cancer cells of Akt by hPEBP4 with its highly expression in TRAIL-resistant prostate cancer cells, promoted us to the of hPEBP4 in the resistance of prostate cancer to in DU145 and cells were highly to the cells hPEBP4 were to hPEBP4 the resistance in prostate cancer. The of a of hPEBP4 the not DU145 cells to is the of hPEBP4 resistance in prostate cancer LNCaP cells to the of hPEBP4 resistance in prostate cancer the resistance the Akt we the cells with for and the cells with Akt not and the of hPEBP4 in DU145 cells LNCaP cells we the to the by hPEBP4 LNCaP cells were with for and with in the of of LNCaP cells, of by hPEBP4 in LNCaP the protein expression of and in the LNCaP cells, and found the expression levels of the hPEBP4 by the expression of hPEBP4 resistance in prostate cancer cells by Akt and hPEBP4 by of Akt and is is a hPEBP4 in prostate cancer cells, we the of and in DU145 with of hPEBP4 in DU145 cells the of but which by of prostate cancer cells of which in we the of hPEBP4 of hPEBP4 in DU145 cells which by resistance in DU145 cells of and the of overexpression of hPEBP4 of and in DU145 cells the protein of as and not and in of and Akt as a which found overexpression of hPEBP4 of the protein of with by the of hPEBP4 protein The hPEBP4 resistance by the expression of which of and the of and is for Akt the of hPEBP4 expression in LNCaP cells of of of and of and the the hPEBP4 of protein expression by resistance by expression of for the Akt in Human hPEBP4 to the and to and in breast cancer cells we to hPEBP4 the to in DU145 cells and LNCaP The and were in the of DU145 cells and LNCaP cells with but not in of cells and the of hPEBP4 with Akt was not not the the and to we the the of by hPEBP4 for the of Akt LNCaP cells were with to we found and the of Akt by hPEBP4 to the of Akt the in DU145 Interestingly, we found and the in to the Akt in prostate cancer understanding of the facilitate prostate cancer and mechanisms in the will to the of for the treatment of prostate cancer. therapeutic potential its to in cancer with not cancer cells with mechanisms to of the resistance are Akt and Akt was in more of of prostate and with prostate cancer levels of in Akt and in cancer cells, and highly activated Akt to correlated with and resistance to in prostate cancer of the of as Akt by a molecule an therapeutic for prostate cancer we by the of prostate cancer the severity of prostate cancer is with expression of which was recently identified as an molecule by us Furthermore, hPEBP4 was highly expressed in TRAIL-resistant LNCaP cells, which show highly levels of but not in TRAIL-sensitive DU145 is overexpression of hPEBP4 in DU145 cells promoted Akt but the DU145 cells to which by of hPEBP4 in TRAIL-resistant LNCaP cells the highly Akt but in to The resistance in LNCaP Thus, of and Akt to for the of the expression of hPEBP4 in prostate cancer to of Akt and of in of treatment for prostate cancer. The of hPEBP4 a for the treatment of levels of prostate cancer cells, which of a which is of and a and the hPEBP4 and but Thus, the of of the of hPEBP4 which by and hPEBP4 to and Here the hPEBP4 with and was in DU145 cells hPEBP4 LNCaP cells with hPEBP4 we not found the of hPEBP4 with Akt the and the of in the of as as the of in the Akt and the of Akt by hPEBP4 in LNCaP in DU145 we not of hPEBP4 and not the hPEBP4 promoted Akt in an will to the of Akt in prostate cancer the we the of resistance in prostate cancer hPEBP4 to and to the facilitate to with the Akt hPEBP4 Akt in Akt in the of and of to the of understanding of the facilitate prostate cancer and mechanisms in the will to the of for the treatment of prostate cancer. therapeutic potential its to in cancer with not cancer cells with mechanisms to of the resistance are Akt and Akt was in more of of prostate and with prostate cancer levels of in Akt and in cancer cells, and highly activated Akt to correlated with and resistance to in prostate cancer of the of as Akt by a molecule an therapeutic for prostate cancer we by the of prostate cancer the severity of prostate cancer is with expression of which was recently identified as an molecule by us Furthermore, hPEBP4 was highly expressed in TRAIL-resistant LNCaP cells, which show highly levels of but not in TRAIL-sensitive DU145 is overexpression of hPEBP4 in DU145 cells promoted Akt but the DU145 cells to which by of hPEBP4 in TRAIL-resistant LNCaP cells the highly Akt but in to The resistance in LNCaP Thus, of and Akt to for the of the expression of hPEBP4 in prostate cancer to of Akt and of in of treatment for prostate cancer. The of hPEBP4 a for the treatment of levels of prostate cancer cells, which of a which is of and a and the hPEBP4 and but Thus, the of of the of hPEBP4 which by and hPEBP4 to and Here the hPEBP4 with and was in DU145 cells hPEBP4 LNCaP cells with hPEBP4 we not found the of hPEBP4 with Akt the and the of in the of as as the of in the Akt and the of Akt by hPEBP4 in LNCaP in DU145 we not of hPEBP4 and not the hPEBP4 promoted Akt in an will to the of Akt in prostate cancer the we the of resistance in prostate cancer hPEBP4 to and to the facilitate to with the Akt hPEBP4 Akt in Akt in the of and of to the of for LNCaP and DU145 and for hPEBP4 of prostate cancer cells by Akt and of