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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

Knockdown of IQGAP1 and/or caveolin-1 suppressed hypercholesterolemia-induced prostate cancer metastasisIn vivo metastasis was assayed for shIQGAP1, shCav1 and shIQ+shCav1 PC-3-luciferase cells in HC-D intraprostatic xenograft model. (a and b) Real-time xenografted primary prostate tumor growth was monitored using whole body in vivo bioluminescence. Scrambled control (Scr-Ctrl, n = 10), IQGAP1 knockdown (shIQGAP1, n = 11), caveolin-1 knockdown (shCav1, n = 11), and double knockdown of IQGAP1 and caveolin-1 (shIQ+shCav1, n = 10). (c) Final prostate tumor weight was assessed after removing seminal vesicles and urinary bladder. Representative figures are shown (Bar, 10 mm). (d) The size of para-aortic lymph nodes was measured. (e) Representative figures show ex vivo bioluminescence imaging for para-aortic lymph nodes (P-LN) and the lung tissues. Ex vivo bioluminescence was measured for secondary metastases in (f) para-aortic lymph nodes, (g) lung and (h) bone. Error bars show standard error of the mean. NS, not significant; *p < 0.05, **p < 0.005, ***p < 0.0005.
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Figure 6: Knockdown of IQGAP1 and/or caveolin-1 suppressed hypercholesterolemia-induced prostate cancer metastasisIn vivo metastasis was assayed for shIQGAP1, shCav1 and shIQ+shCav1 PC-3-luciferase cells in HC-D intraprostatic xenograft model. (a and b) Real-time xenografted primary prostate tumor growth was monitored using whole body in vivo bioluminescence. Scrambled control (Scr-Ctrl, n = 10), IQGAP1 knockdown (shIQGAP1, n = 11), caveolin-1 knockdown (shCav1, n = 11), and double knockdown of IQGAP1 and caveolin-1 (shIQ+shCav1, n = 10). (c) Final prostate tumor weight was assessed after removing seminal vesicles and urinary bladder. Representative figures are shown (Bar, 10 mm). (d) The size of para-aortic lymph nodes was measured. (e) Representative figures show ex vivo bioluminescence imaging for para-aortic lymph nodes (P-LN) and the lung tissues. Ex vivo bioluminescence was measured for secondary metastases in (f) para-aortic lymph nodes, (g) lung and (h) bone. Error bars show standard error of the mean. NS, not significant; *p < 0.05, **p < 0.005, ***p < 0.0005.

Mentions: A total of 42 male NOD/SCID mice were randomly assigned to and xenografted with scrambled control (Scr-Ctrl), IQGAP1 knockdown (shIQGAP1), caveolin-1 knockdown (shCav1) and double knockdown (shIQ+shCa) PC-3 cells. In vivo and ex vivo studies were performed as described in Figure 1a using HC-D. As expected, all groups showed similar body weight (p = 0.21, Supplementary Figure S9a) and serum cholesterol levels (p = 0.96, Supplementary Figure S9b). Whole body in vivo imaging showed similar primary tumor growth curves (p = 0.55, Figure 6a and 6b), and final prostate tumor weight also revealed no significant changes (p = 0.39, Figure 6c) between the groups. Tumor metastases were determined in lymph nodes, lung and bones including joint tissues. Measurement of lymph node size revealed significantly smaller lymph nodes in knockdown groups compared to control (p < 0.0005), but not among knockdown groups (p = 0.8809, Figure 6d). Similarly, ex vivo imaging demonstrated significantly reduced lymph node metastases (Figure 6e and 6f) as well as microscopic lung metastases (Figure 6e and 6g). Pairwise comparisons using Fisher's exact test also demonstrated significantly reduced metastatic invasion to the bones and joints in shIQGAP1 (front limbs; p = 0.0003, rear limbs; p = 0.0005), shCav1 (p = 0.012 and p = 0.0023, respectively), or double knockdown PC-3 cells (p = 0.0095 and p = 0.0012, respectively, Figure 6h). Double knockdown of IQGAP1 and caveolin-1 showed no additive effects in the reduction of metastases (Figure 6f, 6g and 6h) suggesting action via the same molecular pathway. Taken together, these results suggest that IQGAP1 and caveolin-1 potentiate PC-3 metastasis, and that the elevation of IQGAP1 levels in hypercholesterolemia plays an important role in metastasis.


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)

Knockdown of IQGAP1 and/or caveolin-1 suppressed hypercholesterolemia-induced prostate cancer metastasisIn vivo metastasis was assayed for shIQGAP1, shCav1 and shIQ+shCav1 PC-3-luciferase cells in HC-D intraprostatic xenograft model. (a and b) Real-time xenografted primary prostate tumor growth was monitored using whole body in vivo bioluminescence. Scrambled control (Scr-Ctrl, n = 10), IQGAP1 knockdown (shIQGAP1, n = 11), caveolin-1 knockdown (shCav1, n = 11), and double knockdown of IQGAP1 and caveolin-1 (shIQ+shCav1, n = 10). (c) Final prostate tumor weight was assessed after removing seminal vesicles and urinary bladder. Representative figures are shown (Bar, 10 mm). (d) The size of para-aortic lymph nodes was measured. (e) Representative figures show ex vivo bioluminescence imaging for para-aortic lymph nodes (P-LN) and the lung tissues. Ex vivo bioluminescence was measured for secondary metastases in (f) para-aortic lymph nodes, (g) lung and (h) bone. Error bars show standard error of the mean. NS, not significant; *p < 0.05, **p < 0.005, ***p < 0.0005.
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Figure 6: Knockdown of IQGAP1 and/or caveolin-1 suppressed hypercholesterolemia-induced prostate cancer metastasisIn vivo metastasis was assayed for shIQGAP1, shCav1 and shIQ+shCav1 PC-3-luciferase cells in HC-D intraprostatic xenograft model. (a and b) Real-time xenografted primary prostate tumor growth was monitored using whole body in vivo bioluminescence. Scrambled control (Scr-Ctrl, n = 10), IQGAP1 knockdown (shIQGAP1, n = 11), caveolin-1 knockdown (shCav1, n = 11), and double knockdown of IQGAP1 and caveolin-1 (shIQ+shCav1, n = 10). (c) Final prostate tumor weight was assessed after removing seminal vesicles and urinary bladder. Representative figures are shown (Bar, 10 mm). (d) The size of para-aortic lymph nodes was measured. (e) Representative figures show ex vivo bioluminescence imaging for para-aortic lymph nodes (P-LN) and the lung tissues. Ex vivo bioluminescence was measured for secondary metastases in (f) para-aortic lymph nodes, (g) lung and (h) bone. Error bars show standard error of the mean. NS, not significant; *p < 0.05, **p < 0.005, ***p < 0.0005.
Mentions: A total of 42 male NOD/SCID mice were randomly assigned to and xenografted with scrambled control (Scr-Ctrl), IQGAP1 knockdown (shIQGAP1), caveolin-1 knockdown (shCav1) and double knockdown (shIQ+shCa) PC-3 cells. In vivo and ex vivo studies were performed as described in Figure 1a using HC-D. As expected, all groups showed similar body weight (p = 0.21, Supplementary Figure S9a) and serum cholesterol levels (p = 0.96, Supplementary Figure S9b). Whole body in vivo imaging showed similar primary tumor growth curves (p = 0.55, Figure 6a and 6b), and final prostate tumor weight also revealed no significant changes (p = 0.39, Figure 6c) between the groups. Tumor metastases were determined in lymph nodes, lung and bones including joint tissues. Measurement of lymph node size revealed significantly smaller lymph nodes in knockdown groups compared to control (p < 0.0005), but not among knockdown groups (p = 0.8809, Figure 6d). Similarly, ex vivo imaging demonstrated significantly reduced lymph node metastases (Figure 6e and 6f) as well as microscopic lung metastases (Figure 6e and 6g). Pairwise comparisons using Fisher's exact test also demonstrated significantly reduced metastatic invasion to the bones and joints in shIQGAP1 (front limbs; p = 0.0003, rear limbs; p = 0.0005), shCav1 (p = 0.012 and p = 0.0023, respectively), or double knockdown PC-3 cells (p = 0.0095 and p = 0.0012, respectively, Figure 6h). Double knockdown of IQGAP1 and caveolin-1 showed no additive effects in the reduction of metastases (Figure 6f, 6g and 6h) suggesting action via the same molecular pathway. Taken together, these results suggest that IQGAP1 and caveolin-1 potentiate PC-3 metastasis, and that the elevation of IQGAP1 levels in hypercholesterolemia plays an important role in metastasis.

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