Prostate Cancer Cell-Adipocyte Interaction

Abstract

Prostate cancer is one of the leading causes of death among men in the United States, and acquisition of hormone resistance (androgen independence) by cancer cells is a fatal event during the natural history of prostate cancer. Obesity is another serious health problem and has been shown to be associated with prostate cancer. However, little is known about the molecular basis of this association. Here we show that factor(s) secreted from adipocytes stimulate prostate cancer cell proliferation. Leptin is one of the major adipose cytokines, and it controls body weight homeostasis through food intake and energy expenditure. We identify leptin as a novel growth factor in androgen-independent prostate cancer cell growth. Strikingly, leptin stimulates cell proliferation specifically in androgen-independent DU145 and PC-3 prostate cancer cells but not in androgen-dependent LNCaP-FGC cells, although both cell types express functional leptin receptor isoforms. c-Jun NH2-terminal kinase (JNK) has been shown recently to play a crucial in and leptin in androgen-independent prostate cancer cells, and the of the leptin of androgen-independent prostate cancer cell proliferation. that is androgen-independent prostate cancer cell proliferation. by adipocytes and body weight homeostasis with leptin in androgen-independent prostate cancer cell and growth factor and the leptin of androgen-independent prostate cancer cell adipose cytokines, as as and prostate cancer and be Prostate cancer is one of the leading causes of death among men in the United States, and acquisition of hormone resistance (androgen independence) by cancer cells is a fatal event during the natural history of prostate cancer. Obesity is another serious health problem and has been shown to be associated with prostate cancer. However, little is known about the molecular basis of this association. Here we show that factor(s) secreted from adipocytes stimulate prostate cancer cell proliferation. Leptin is one of the major adipose cytokines, and it controls body weight homeostasis through food intake and energy expenditure. We identify leptin as a novel growth factor in androgen-independent prostate cancer cell growth. Strikingly, leptin stimulates cell proliferation specifically in androgen-independent DU145 and PC-3 prostate cancer cells but not in androgen-dependent LNCaP-FGC cells, although both cell types express functional leptin receptor isoforms. c-Jun NH2-terminal kinase (JNK) has been shown recently to play a crucial in and leptin in androgen-independent prostate cancer cells, and the of the leptin of androgen-independent prostate cancer cell proliferation. that is androgen-independent prostate cancer cell proliferation. by adipocytes and body weight homeostasis with leptin in androgen-independent prostate cancer cell and growth factor and the leptin of androgen-independent prostate cancer cell adipose cytokines, as as and prostate cancer and be Prostate cancer is one of the leading causes of death among men in the United is by a natural a of with is to as a growth the prostate cancer. this is in the of the to the of and in in the death of the it is to and prostate of that is a factor prostate cancer. is associated with of of prostate a with and cancer and of prostate cancer in a has been shown associated with of prostate cancer However, little is known about the molecular basis of is that adipocytes and We that adipose prostate cancer cells and cancer one of the major by controls body weight homeostasis through food intake and energy in the leptin receptor in and to body weight leptin is in and and has been to cell proliferation in cells cancer cells to cell leptin through the of of leptin receptor a receptor of the receptor of leptin receptor been in the and the to been in the and the and the of and of and of c-Jun NH2-terminal growth growth and of c-Jun NH2-terminal growth growth and kinase and the is to but not leptin has been shown of the c-Jun NH2-terminal kinase (JNK) of has been in in leptin receptor has been in and prostate although not been one of the kinase and kinase is in to and and and of as and to the and the and of c-Jun c-Jun in is a of that to the and factor the the as as to the of cell proliferation and during and and has been recently to play a crucial in and has been shown in cell proliferation and in androgen-independent prostate cancer PC-3 cells However, to growth been to the cell cell of prostate cancer cells is not the that is by adipocytes and a both in body weight homeostasis and androgen-independent prostate cancer cell growth. is secreted from adipocytes in to cell types with to body and with in in with prostate cancer as with with cancer with the is secreted by androgen-independent prostate cancer cells but not by androgen-dependent cells as as stimulates androgen-independent prostate cancer cell growth. that stimulate androgen-independent prostate cancer cell growth in both and growth factor is in energy homeostasis associated with prostate cancer and the of prostate cancer is secreted by prostate cancer cells and androgen-independent prostate cancer cell growth in both and this we DU145 and PC-3 cells as androgen-independent prostate cancer cells and LNCaP-FGC cells androgen-dependent prostate cancer cells, and that adipose stimulate prostate cancer cell proliferation. We identify leptin as a novel growth factor in androgen-independent prostate cancer cell proliferation and show that androgen-independent prostate cancer cell proliferation. we identify of leptin with and in androgen-independent prostate cancer cell proliferation. adipose cytokines, as and prostate cancer and and and leptin from a and from and from and prostate cancer cell and LNCaP-FGC from the DU145 cells in with and PC-3 and LNCaP-FGC cells in with and from and in growth with and the of in and and to and of the cells with and with the to cell and identify cells with with and a as PC-3 and LNCaP-FGC cells of by with leptin cells with to as in with of during the with with with and in in and the as PC-3 and cells in to of and in the with leptin to to a of of cells in and and by a and and in and the as by the of leptin receptor from and LNCaP-FGC cells of to in a to the of of of and of the with by of and of of that in a of the leptin with as and as and and by a with prostate cancer cells in the and by leptin the cells with to as with by a and in the cell and and with and the as a cell and of c-Jun of and to the the and with that specifically a of a and with that both and to the to the in of cell with of by a of the c-Jun and as a with the cell the in of the kinase by of the c-Jun by and by as in cell by to of in Prostate in to a prostate cancer cells and with by leptin of cells as that factor(s) by adipocytes prostate cancer we from stimulates cell proliferation in prostate cancer cells a We to adipocytes in by cells with and as with that cells the from to Prostate cancer cells with from cell Strikingly, the from in both androgen-independent DU145 and PC-3 cells and androgen-dependent LNCaP-FGC cells, that from that adipose factor(s) cell proliferation both in androgen-independent and prostate cancer is one of the major secreted from adipocytes We the of leptin receptor in the prostate cancer cell that and LNCaP-FGC cells express both of the functional and is with a that prostate cancer leptin leptin prostate cancer cell we the of leptin in prostate cancer Leptin in a to in androgen-independent DU145 and PC-3 cells Leptin stimulate with cell proliferation in prostate cancer this we the a cell growth that the of by with leptin cells in androgen-independent in DU145 and PC-3 cells that with cell growth in androgen-independent prostate cancer is the that leptin as a growth factor in androgen-independent prostate cancer cell growth. leptin not cell in androgen-dependent LNCaP-FGC cells and of leptin receptor in prostate cancer the of leptin receptor in and LNCaP-FGC Leptin receptor has and cells of and to with and and and stimulates cell proliferation in androgen-independent DU145 and PC-3 prostate cancer cells but not in androgen-dependent LNCaP-FGC and LNCaP-FGC cells and with the of leptin during the the of of a and LNCaP-FGC cells of and with leptin by the of during the the of of a is to We of in prostate cancer cells with leptin to that leptin in DU145 and PC-3 in cell leptin in DU145 cells, of leptin and to the by leptin a in PC-3 in LNCaP-FGC cells as However, leptin not in LNCaP-FGC to androgen-independent prostate cancer cell proliferation in to in androgen-independent DU145 and PC-3 prostate cancer cells but not in androgen-dependent LNCaP-FGC DU145 and PC-3 prostate cancer cells and androgen-dependent LNCaP-FGC cells of and in and the leptin and and as a to stimulate to the in with c-Jun as a of the by the c-Jun to cell to the that both and of and is c-Jun and in and of is crucial the and of c-Jun We c-Jun in DU145 and PC-3 cells during androgen-independent cell proliferation. c-Jun both in DU145 and PC-3 cells, and of leptin c-Jun in with stimulates of during androgen-independent prostate cancer cell proliferation. DU145 and PC-3 prostate cancer cells and with leptin and and and and cells as and to c-Jun and with and and c-Jun to of c-Jun with and with the that both and of c-Jun androgen-independent cell we the of the leptin of as as c-Jun in DU145 and PC-3 that from to a the leptin of c-Jun and in a in both DU145 and PC-3 cell proliferation the of in cell that leptin androgen-independent cell proliferation in DU145 and PC-3 cells through c-Jun is to that is to and to the of cell proliferation as with of the c-Jun in cell growth and is in the of cell proliferation in DU145 and PC-3 cells is with a that by cell proliferation and in PC-3 cells the of leptin is the that has been to stimulate prostate cancer cell growth is androgen-independent prostate cancer cell proliferation. androgen-independent DU145 and PC-3 prostate cancer cells of and with leptin with and and with a and and with and as of c-Jun and by with and and c-Jun to of c-Jun and with the that both and of c-Jun a DU145 and PC-3 cells with by leptin proliferation by during the the of of a the of leptin with adipose in androgen-independent prostate cancer cell we cells with with shown cell proliferation in androgen-independent DU145 and PC-3 cells but in androgen-dependent LNCaP-FGC cells Leptin the of androgen-independent prostate cancer cell proliferation in DU145 and PC-3 cells, but it not the of LNCaP-FGC cell proliferation with cell proliferation in DU145 and PC-3 cells but not LNCaP-FGC cell proliferation Strikingly, leptin the of prostate cancer cell proliferation in DU145 and PC-3 cells, with leptin and not LNCaP-FGC cell proliferation that leptin a crucial in androgen-independent prostate cancer cell growth in with adipose of leptin with and in androgen-independent prostate cancer cell proliferation. and LNCaP-FGC cells and with leptin in with proliferation by during the the of of a from adipose cell proliferation in prostate cancer cells with the of with prostate cancer this that prostate cancer cell growth by adipose the we that one of the major adipose cytokines, controls body weight homeostasis through food intake and energy androgen-independent prostate cancer cell proliferation and to adipose as and been shown associated with both body weight homeostasis and prostate cancer as as with prostate cancer cell growth in androgen-independent DU145 and PC-3 cells but not in androgen-dependent LNCaP-FGC cells and we of and with leptin in the androgen-independent of prostate cancer cell proliferation. the leptin of androgen-independent prostate cancer cell proliferation that adipose with to growth in prostate cancer in adipose prostate cancer cell growth to However, adipose be cancer cells to adipose cancer cells with of Prostate cancer cells be to adipose the to is with the that associated with the of prostate cancer cell proliferation in androgen-dependent LNCaP-FGC cells and and and although the from cell proliferation in both LNCaP-FGC cells and androgen-independent DU145 and PC-3 cells that adipose and to growth in LNCaP-FGC not to androgen-independent cell growth but to the of by prostate cancer is another that is by adipocytes and in the of resistance has been that in androgen-dependent cells through of receptor that play a in the of androgen-independent in prostate cancer to adipose as and has been recently to play a in and is in and in and receptor in has been that is crucial in prostate cancer cell proliferation and Here we identify leptin as of in androgen-independent prostate cancer DU145 and PC-3 cells and show that leptin androgen-independent cell proliferation leptin and as as and in resistance and prostate cancer. prostate in the and resistance in be as as as is associated with to prostate cancer we be to and prostate in the by through with as Prostate cancer is one of the leading causes of death among men in the United is by a natural a of with is to as a growth the prostate cancer. this is in the of the to the of and in in the death of the it is to and prostate cancer. of that is a factor prostate cancer. is associated with of of prostate a with and cancer and of prostate cancer in a has been shown associated with of prostate cancer However, little is known about the molecular basis of is that adipocytes and We that adipose prostate cancer cells and cancer one of the major by controls body weight homeostasis through food intake and energy in the leptin receptor in and to body weight leptin is in and and has been to cell proliferation in cells cancer cells to cell leptin through the of of leptin receptor a receptor of the receptor of leptin receptor been in the and the to been in the and the and the of and of and of c-Jun NH2-terminal growth growth and of c-Jun NH2-terminal growth growth and kinase and the is to but not leptin has been shown of the c-Jun NH2-terminal kinase (JNK) of has been in in leptin receptor has been in and prostate although not been one of the kinase and kinase is in to and and and of as and to the and the and of c-Jun c-Jun in is a of that to the and factor the the as as to the of cell proliferation and during and and has been recently to play a crucial in and has been shown in cell proliferation and in androgen-independent prostate cancer PC-3 cells However, to growth been to the cell cell of prostate cancer cells Leptin is not the that is by adipocytes and a both in body weight homeostasis and androgen-independent prostate cancer cell growth. is secreted from adipocytes in to cell types with to body and with in in with prostate cancer as with with cancer with the is secreted by androgen-independent prostate cancer cells but not by androgen-dependent cells as as stimulates androgen-independent prostate cancer cell growth. that stimulate androgen-independent prostate cancer cell growth in both and growth factor is in energy homeostasis associated with prostate cancer and the of prostate cancer is secreted by prostate cancer cells and androgen-independent prostate cancer cell growth in both and this we DU145 and PC-3 cells as androgen-independent prostate cancer cells and LNCaP-FGC cells androgen-dependent prostate cancer cells, and that adipose stimulate prostate cancer cell proliferation. We identify leptin as a novel growth factor in androgen-independent prostate cancer cell proliferation and show that androgen-independent prostate cancer cell proliferation. we identify of leptin with and in androgen-independent prostate cancer cell proliferation. adipose cytokines, as and prostate cancer and and and leptin from a and from and from and prostate cancer cell and LNCaP-FGC from the DU145 cells in with and PC-3 and LNCaP-FGC cells in with and from and in growth with and the of in and and to and of the cells with and with the to cell and identify cells with with and a as PC-3 and LNCaP-FGC cells of by with leptin cells with to as in with of during the with with with and in in and the as PC-3 and cells in to of and in the with leptin to to a of of cells in and and by a and and in and the as by the of leptin receptor from and LNCaP-FGC cells of to in a to the of of of and of the with by of and of of that in a of the leptin with as and as and and by a with prostate cancer cells in the and by leptin the cells with to as with by a and in the cell and and with and the as a cell and of c-Jun of and to the the and with that specifically a of a and with that both and to the to the in of cell with of by a of the c-Jun and as a with the cell the in of the kinase by of the c-Jun by and by as in cell by to of in Prostate in to a prostate cancer cells and with by leptin of cells as and and leptin from a and from and from Prostate and prostate cancer cell and LNCaP-FGC from the DU145 cells in with and PC-3 and LNCaP-FGC cells in with and from and in growth with and the of in and and to and of the cells with and with the to cell and identify cells with with and a as PC-3 and LNCaP-FGC cells of by with leptin cells with to as in with of during the with with with and in in and the as PC-3 and cells in to of and in the with leptin to to a of of cells in and and by a and and in and the as by the of leptin receptor from and LNCaP-FGC cells of to in a to the of of of and of the with by of and of of that in a of the leptin with as and as and and by a with prostate cancer cells in the and by leptin the cells with to as with by a and in the cell and and with and the as a cell and of c-Jun of and to the the and with that specifically a of a and with that both and to the to the in of cell with of by a of the c-Jun and as a with the cell the in of the kinase by of the c-Jun by and by as in cell by to of in Prostate in to a prostate cancer cells and with by leptin of cells as that factor(s) by adipocytes prostate cancer we from stimulates cell proliferation in prostate cancer cells a We to adipocytes in by cells with and as with that cells the from to Prostate cancer cells with from cell Strikingly, the from in both androgen-independent DU145 and PC-3 cells and androgen-dependent LNCaP-FGC cells, that from that adipose factor(s) cell proliferation both in androgen-independent and prostate cancer is one of the major secreted from adipocytes We the of leptin receptor in the prostate cancer cell that and LNCaP-FGC cells express both of the functional and is with a that prostate cancer leptin leptin prostate cancer cell we the of leptin in prostate cancer Leptin in a to in androgen-independent DU145 and PC-3 cells Leptin stimulate with cell proliferation in prostate cancer this we the a cell growth that the of by with leptin cells in androgen-independent in DU145 and PC-3 cells that with cell growth in androgen-independent prostate cancer is the that leptin as a growth factor in androgen-independent prostate cancer cell growth. leptin not cell in androgen-dependent LNCaP-FGC cells and stimulates cell proliferation in androgen-independent DU145 and PC-3 prostate cancer cells but not in androgen-dependent LNCaP-FGC and LNCaP-FGC cells and with the of leptin during the the of of a and LNCaP-FGC cells of and with leptin by the of during the the of of a is to We of in prostate cancer cells with leptin to that leptin in DU145 and PC-3 in cell leptin in DU145 cells, of leptin and to the by leptin a in PC-3 in LNCaP-FGC cells as However, leptin not in LNCaP-FGC to androgen-independent prostate cancer cell proliferation in to in androgen-independent DU145 and PC-3 prostate cancer cells but not in androgen-dependent LNCaP-FGC DU145 and PC-3 prostate cancer cells and androgen-dependent LNCaP-FGC cells of and in and the leptin and and as a to stimulate to the in with c-Jun as a of the by the c-Jun to cell to the that both and of and is c-Jun and in and of is crucial the and of c-Jun We c-Jun in DU145 and PC-3 cells during androgen-independent cell proliferation. c-Jun both in DU145 and PC-3 cells, and of leptin c-Jun in with stimulates of during androgen-independent prostate cancer cell proliferation. DU145 and PC-3 prostate cancer cells and with leptin and and and and cells as and to c-Jun and with and and c-Jun to of c-Jun with and with the that both and of c-Jun androgen-independent cell we the of the leptin of as as c-Jun in DU145 and PC-3 that from to a the leptin of c-Jun and in a in both DU145 and PC-3 cell proliferation the of in cell that leptin androgen-independent cell proliferation in DU145 and PC-3 cells through c-Jun is to that is to and to the of cell proliferation as with of the c-Jun in cell growth and is in the of cell proliferation in DU145 and PC-3 cells is with a that by cell proliferation and in PC-3 cells the of leptin is the that has been to stimulate prostate cancer cell growth is androgen-independent prostate cancer cell proliferation. androgen-independent DU145 and PC-3 prostate cancer cells of and with leptin with and and with a and and with and as of c-Jun and by with and and c-Jun to of c-Jun and with the that both and of c-Jun a DU145 and PC-3 cells with by leptin proliferation by during the the of of a the of leptin with adipose in androgen-independent prostate cancer cell we cells with with shown cell proliferation in androgen-independent DU145 and PC-3 cells but in androgen-dependent LNCaP-FGC cells Leptin the of androgen-independent prostate cancer cell proliferation in DU145 and PC-3 cells, but it not the of LNCaP-FGC cell proliferation with cell proliferation in DU145 and PC-3 cells but not LNCaP-FGC cell proliferation Strikingly, leptin the of prostate cancer cell proliferation in DU145 and PC-3 cells, with leptin and not LNCaP-FGC cell proliferation that leptin a crucial in androgen-independent prostate cancer cell growth in with adipose of leptin with and in androgen-independent prostate cancer cell proliferation. and LNCaP-FGC cells and with leptin in with proliferation by during the the of of a that factor(s) by adipocytes prostate cancer we from stimulates cell proliferation in prostate cancer cells a We to adipocytes in by cells with and as with that cells the from to Prostate cancer cells with from cell Strikingly, the from in both androgen-independent DU145 and PC-3 cells and androgen-dependent LNCaP-FGC cells, that from that adipose factor(s) cell proliferation both in androgen-independent and prostate cancer Leptin is one of the major secreted from adipocytes We the of leptin receptor in the prostate cancer cell that and LNCaP-FGC cells express both of the functional and is with a that prostate cancer leptin leptin prostate cancer cell we the of leptin in prostate cancer Leptin in a to in androgen-independent DU145 and PC-3 cells Leptin stimulate with cell proliferation in prostate cancer this we the a cell growth that the of by with leptin cells in androgen-independent in DU145 and PC-3 cells that with cell growth in androgen-independent prostate cancer is the that leptin as a growth factor in androgen-independent prostate cancer cell growth. leptin not cell in androgen-dependent LNCaP-FGC cells and Leptin is to We of in prostate cancer cells with leptin to that leptin in DU145 and PC-3 in cell leptin in DU145 cells, of leptin and to the by leptin a in PC-3 in LNCaP-FGC cells as However, leptin not in LNCaP-FGC to androgen-independent prostate cancer cell proliferation in to c-Jun is c-Jun and in and of is crucial the and of c-Jun We c-Jun in DU145 and PC-3 cells during androgen-independent cell proliferation. c-Jun both in DU145 and PC-3 cells, and of leptin c-Jun in with androgen-independent cell we the of the leptin of as as c-Jun in DU145 and PC-3 that from to a the leptin of c-Jun and in a in both DU145 and PC-3 cell proliferation the of in cell that leptin androgen-independent cell proliferation in DU145 and PC-3 cells through c-Jun is to that is to and to the of cell proliferation as with of the c-Jun in cell growth and is in the of cell proliferation in DU145 and PC-3 cells is with a that by cell proliferation and in PC-3 cells the of leptin is the that has been to stimulate prostate cancer cell growth the of leptin with adipose in androgen-independent prostate cancer cell we cells with with shown cell proliferation in androgen-independent DU145 and PC-3 cells but in androgen-dependent LNCaP-FGC cells Leptin the of androgen-independent prostate cancer cell proliferation in DU145 and PC-3 cells, but it not the of LNCaP-FGC cell proliferation with cell proliferation in DU145 and PC-3 cells but not LNCaP-FGC cell proliferation Strikingly, leptin the of prostate cancer cell proliferation in DU145 and PC-3 cells, with leptin and not LNCaP-FGC cell proliferation that leptin a crucial in androgen-independent prostate cancer cell growth in with adipose from adipose cell proliferation in prostate cancer cells with the of with prostate cancer this that prostate cancer cell growth by adipose the we that one of the major adipose cytokines, controls body weight homeostasis through food intake and energy androgen-independent prostate cancer cell proliferation and to adipose as and been shown associated with both body weight homeostasis and prostate cancer as as with prostate cancer cell growth in androgen-independent DU145 and PC-3 cells but not in androgen-dependent LNCaP-FGC cells and we of and with leptin in the androgen-independent of prostate cancer cell proliferation. the leptin of androgen-independent prostate cancer cell proliferation that adipose with to growth in prostate cancer in adipose prostate cancer cell growth to However, adipose be cancer cells to adipose cancer cells with of Prostate cancer cells be to adipose the to is with the that associated with the of prostate cancer cell proliferation in androgen-dependent LNCaP-FGC cells and and and although the from cell proliferation in both LNCaP-FGC cells and androgen-independent DU145 and PC-3 cells that adipose and to growth in LNCaP-FGC not to androgen-independent cell growth but to the of by prostate cancer is another that is by adipocytes and in the of resistance has been that in androgen-dependent cells through of receptor that play a in the of androgen-independent in prostate cancer to adipose as and has been recently to play a in and is in and in and receptor in has been that is crucial in prostate cancer cell proliferation and Here we identify leptin as of in androgen-independent prostate cancer DU145 and PC-3 cells and show that leptin androgen-independent cell proliferation leptin and as as and in resistance and prostate cancer. prostate in the and resistance in be as as as is associated with to prostate cancer we be to and prostate in the by through with as from adipose cell proliferation in prostate cancer cells with the of with prostate cancer this that prostate cancer cell growth by adipose the we that one of the major adipose cytokines, controls body weight homeostasis through food intake and energy androgen-independent prostate cancer cell proliferation and to adipose as and been shown associated with both body weight homeostasis and prostate cancer as as with prostate cancer cell growth in androgen-independent DU145 and PC-3 cells but not in androgen-dependent LNCaP-FGC cells and we of and with leptin in the androgen-independent of prostate cancer cell proliferation. the leptin of androgen-independent prostate cancer cell proliferation that adipose with to growth in prostate cancer in adipose prostate cancer cell growth to However, adipose be cancer cells to adipose cancer cells with of Prostate cancer cells be to adipose the to is with the that associated with the of prostate cancer cell proliferation in androgen-dependent LNCaP-FGC cells and and and although the from cell proliferation in both LNCaP-FGC cells and androgen-independent DU145 and PC-3 cells that adipose and to growth in LNCaP-FGC not to androgen-independent cell growth but to the of by prostate cancer is another that is by adipocytes and in the of resistance has been that in androgen-dependent cells through of receptor that play a in the of androgen-independent in prostate cancer to adipose as and has been recently to play a in and is in and in and receptor in has been that is crucial in prostate cancer cell proliferation and Here we identify leptin as of in androgen-independent prostate cancer DU145 and PC-3 cells and show that leptin androgen-independent cell proliferation leptin and as as and in resistance and prostate cancer. prostate in the and resistance in be as as as is associated with to prostate cancer we be to and prostate in the by through with as We in and of this