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Diet-induced hypercholesterolemia promotes androgen-independent prostate cancer metastasis via IQGAP1 and caveolin-1.

Moon H, Ruelcke JE, Choi E, Sharpe LJ, Nassar ZD, Bielefeldt-Ohmann H, Parat MO, Shah A, Francois M, Inder KL, Brown AJ, Russell PJ, Parton RG, Hill MM - Oncotarget (2015)

Bottom Line: Obesity and metabolic syndrome are associated with several cancers, however, the molecular mechanisms remain to be fully elucidated.Down-regulation of caveolin-1 or IQGAP1 in PC-3 cells reduced migration and invasion in vitro, and hypercholesterolemia-induced metastasis in vivo.Double knock-down of caveolin-1 and IQGAP1 showed no additive effect, suggesting that caveolin-1 and IQGAP1 act via the same pathway.

View Article: PubMed Central - PubMed

Affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.

ABSTRACT
Obesity and metabolic syndrome are associated with several cancers, however, the molecular mechanisms remain to be fully elucidated. Recent studies suggest that hypercholesterolemia increases intratumoral androgen signaling in prostate cancer, but it is unclear whether androgen-independent mechanisms also exist. Since hypercholesterolemia is associated with advanced, castrate-resistant prostate cancer, in this study, we aimed to determine whether and how hypercholesterolemia affects prostate cancer progression in the absence of androgen signaling. We demonstrate that diet-induced hypercholesterolemia promotes orthotopic xenograft PC-3 cell metastasis, concomitant with elevated expression of caveolin-1 and IQGAP1 in xenograft tumor tissues. In vitro cholesterol treatment of PC-3 cells stimulated migration and increased IQGAP1 and caveolin-1 protein level and localization to a detergent-resistant fraction. Down-regulation of caveolin-1 or IQGAP1 in PC-3 cells reduced migration and invasion in vitro, and hypercholesterolemia-induced metastasis in vivo. Double knock-down of caveolin-1 and IQGAP1 showed no additive effect, suggesting that caveolin-1 and IQGAP1 act via the same pathway. Taken together, our data show that hypercholesterolemia promotes prostate cancer metastasis independent of the androgen pathway, in part by increasing IQGAP1 and caveolin-1. These results have broader implications for managing metastasis of cancers in general as IQGAP1 and hypercholesterolemia are implicated in the progression of several cancers.

No MeSH data available.


Related in: MedlinePlus

Diet-induced hypercholesterolemia promotes androgen-independent prostate cancer metastasis but not primary tumor growth(a) Experimental plan. Fourteen days prior to xenografting, male NOD/SCID mice were randomly allocated to low-cholesterol normal diet (LC-D, n = 14) or to a hypercholesterolemic diet (HC-D, n = 15). On day 0, human prostate cancer PC-3 expressing the luciferase gene were orthotopically injected into the dorsolateral prostate glands. (b) Serum cholesterol, (c) body weight and (d and e) primary tumor growth was measured by in vivo bioluminescence imaging on the indicated days during the course of the experiment. (f) At the end of the experiment, primary prostate tumors were weighed after removing seminal vesicles and the urinary bladder. Ex vivo imaging was used to measure metastasis in (g) para-aortic lymph node (P-LN), (h) mesenteric lymph node (M-LN), (i) lung, and (j) bone. Error bars show standard error of the mean. NS, not significant; *p < 0.05; **p < 0.005; ***p < 0.0005. Group comparison in (j) used Fisher's exact test, **p < 0.005.
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Figure 1: Diet-induced hypercholesterolemia promotes androgen-independent prostate cancer metastasis but not primary tumor growth(a) Experimental plan. Fourteen days prior to xenografting, male NOD/SCID mice were randomly allocated to low-cholesterol normal diet (LC-D, n = 14) or to a hypercholesterolemic diet (HC-D, n = 15). On day 0, human prostate cancer PC-3 expressing the luciferase gene were orthotopically injected into the dorsolateral prostate glands. (b) Serum cholesterol, (c) body weight and (d and e) primary tumor growth was measured by in vivo bioluminescence imaging on the indicated days during the course of the experiment. (f) At the end of the experiment, primary prostate tumors were weighed after removing seminal vesicles and the urinary bladder. Ex vivo imaging was used to measure metastasis in (g) para-aortic lymph node (P-LN), (h) mesenteric lymph node (M-LN), (i) lung, and (j) bone. Error bars show standard error of the mean. NS, not significant; *p < 0.05; **p < 0.005; ***p < 0.0005. Group comparison in (j) used Fisher's exact test, **p < 0.005.

Mentions: To determine the direct but androgen-independent effects of hypercholesterolemia on advanced prostate cancer progression, we used an androgen-receptor negative prostate cancer cell line PC-3, expressing the luciferase gene (Supplementary Figure S1) in an orthotopic xenograft mouse model. Male NOD/SCID mice were randomly assigned to low-cholesterol normal (LC-D) and isocaloric hypercholesterolemic diet (HC-D) groups. Two weeks after diet initiation, in vivo and ex vivo studies were performed as illustrated in (Figure 1a). Similar to previous studies [7, 10], serum cholesterol levels (Figure 1b) but not body weights (Figure 1c) were significantly increased in the HC-D group. However, the intensity of in vivo bioluminescence (p = 0.87, Figure 1d and 1e) and final prostate tumor weights (p = 0.23, Figure 1f) were not significantly different between the groups, although the HC-D group showed an increased trend.


Diet-induced hypercholesterolemia promotes androgen-independent prostate cancer metastasis via IQGAP1 and caveolin-1.

Moon H, Ruelcke JE, Choi E, Sharpe LJ, Nassar ZD, Bielefeldt-Ohmann H, Parat MO, Shah A, Francois M, Inder KL, Brown AJ, Russell PJ, Parton RG, Hill MM - Oncotarget (2015)

Diet-induced hypercholesterolemia promotes androgen-independent prostate cancer metastasis but not primary tumor growth(a) Experimental plan. Fourteen days prior to xenografting, male NOD/SCID mice were randomly allocated to low-cholesterol normal diet (LC-D, n = 14) or to a hypercholesterolemic diet (HC-D, n = 15). On day 0, human prostate cancer PC-3 expressing the luciferase gene were orthotopically injected into the dorsolateral prostate glands. (b) Serum cholesterol, (c) body weight and (d and e) primary tumor growth was measured by in vivo bioluminescence imaging on the indicated days during the course of the experiment. (f) At the end of the experiment, primary prostate tumors were weighed after removing seminal vesicles and the urinary bladder. Ex vivo imaging was used to measure metastasis in (g) para-aortic lymph node (P-LN), (h) mesenteric lymph node (M-LN), (i) lung, and (j) bone. Error bars show standard error of the mean. NS, not significant; *p < 0.05; **p < 0.005; ***p < 0.0005. Group comparison in (j) used Fisher's exact test, **p < 0.005.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: Diet-induced hypercholesterolemia promotes androgen-independent prostate cancer metastasis but not primary tumor growth(a) Experimental plan. Fourteen days prior to xenografting, male NOD/SCID mice were randomly allocated to low-cholesterol normal diet (LC-D, n = 14) or to a hypercholesterolemic diet (HC-D, n = 15). On day 0, human prostate cancer PC-3 expressing the luciferase gene were orthotopically injected into the dorsolateral prostate glands. (b) Serum cholesterol, (c) body weight and (d and e) primary tumor growth was measured by in vivo bioluminescence imaging on the indicated days during the course of the experiment. (f) At the end of the experiment, primary prostate tumors were weighed after removing seminal vesicles and the urinary bladder. Ex vivo imaging was used to measure metastasis in (g) para-aortic lymph node (P-LN), (h) mesenteric lymph node (M-LN), (i) lung, and (j) bone. Error bars show standard error of the mean. NS, not significant; *p < 0.05; **p < 0.005; ***p < 0.0005. Group comparison in (j) used Fisher's exact test, **p < 0.005.
Mentions: To determine the direct but androgen-independent effects of hypercholesterolemia on advanced prostate cancer progression, we used an androgen-receptor negative prostate cancer cell line PC-3, expressing the luciferase gene (Supplementary Figure S1) in an orthotopic xenograft mouse model. Male NOD/SCID mice were randomly assigned to low-cholesterol normal (LC-D) and isocaloric hypercholesterolemic diet (HC-D) groups. Two weeks after diet initiation, in vivo and ex vivo studies were performed as illustrated in (Figure 1a). Similar to previous studies [7, 10], serum cholesterol levels (Figure 1b) but not body weights (Figure 1c) were significantly increased in the HC-D group. However, the intensity of in vivo bioluminescence (p = 0.87, Figure 1d and 1e) and final prostate tumor weights (p = 0.23, Figure 1f) were not significantly different between the groups, although the HC-D group showed an increased trend.

Bottom Line: Obesity and metabolic syndrome are associated with several cancers, however, the molecular mechanisms remain to be fully elucidated.Down-regulation of caveolin-1 or IQGAP1 in PC-3 cells reduced migration and invasion in vitro, and hypercholesterolemia-induced metastasis in vivo.Double knock-down of caveolin-1 and IQGAP1 showed no additive effect, suggesting that caveolin-1 and IQGAP1 act via the same pathway.

View Article: PubMed Central - PubMed

Affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.

ABSTRACT
Obesity and metabolic syndrome are associated with several cancers, however, the molecular mechanisms remain to be fully elucidated. Recent studies suggest that hypercholesterolemia increases intratumoral androgen signaling in prostate cancer, but it is unclear whether androgen-independent mechanisms also exist. Since hypercholesterolemia is associated with advanced, castrate-resistant prostate cancer, in this study, we aimed to determine whether and how hypercholesterolemia affects prostate cancer progression in the absence of androgen signaling. We demonstrate that diet-induced hypercholesterolemia promotes orthotopic xenograft PC-3 cell metastasis, concomitant with elevated expression of caveolin-1 and IQGAP1 in xenograft tumor tissues. In vitro cholesterol treatment of PC-3 cells stimulated migration and increased IQGAP1 and caveolin-1 protein level and localization to a detergent-resistant fraction. Down-regulation of caveolin-1 or IQGAP1 in PC-3 cells reduced migration and invasion in vitro, and hypercholesterolemia-induced metastasis in vivo. Double knock-down of caveolin-1 and IQGAP1 showed no additive effect, suggesting that caveolin-1 and IQGAP1 act via the same pathway. Taken together, our data show that hypercholesterolemia promotes prostate cancer metastasis independent of the androgen pathway, in part by increasing IQGAP1 and caveolin-1. These results have broader implications for managing metastasis of cancers in general as IQGAP1 and hypercholesterolemia are implicated in the progression of several cancers.

No MeSH data available.


Related in: MedlinePlus