Impact of circulating cholesterol levels on growth and intratumoral androgen concentration of prostate tumors.
Prostate cancer (PCa) is the second most common cancer in men. Androgen deprivation therapy (ADT) leads to tumor involution and reduction of tumor burden. However, tumors eventually reemerge that have overcome the absence of gonadal androgens, termed castration resistant PCa (CRPC). Theories underly...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3261168?pdf=render |
| _version_ | 1828868090971029504 |
|---|---|
| author | Elahe A Mostaghel Keith R Solomon Kristine Pelton Michael R Freeman R Bruce Montgomery |
| author_facet | Elahe A Mostaghel Keith R Solomon Kristine Pelton Michael R Freeman R Bruce Montgomery |
| author_sort | Elahe A Mostaghel |
| collection | DOAJ |
| description | Prostate cancer (PCa) is the second most common cancer in men. Androgen deprivation therapy (ADT) leads to tumor involution and reduction of tumor burden. However, tumors eventually reemerge that have overcome the absence of gonadal androgens, termed castration resistant PCa (CRPC). Theories underlying the development of CRPC include androgen receptor (AR) mutation allowing for promiscuous activation by non-androgens, AR amplification and overexpression leading to hypersensitivity to low androgen levels, and/or tumoral uptake and conversion of adrenally derived androgens. More recently it has been proposed that prostate tumor cells synthesize their own androgens through de novo steroidogenesis, which involves the step-wise synthesis of androgens from cholesterol. Using the in vivo LNCaP PCa xenograft model, previous data from our group demonstrated that a hypercholesterolemia diet potentiates prostatic tumor growth via induction of angiogenesis. Using this same model we now demonstrate that circulating cholesterol levels are significantly associated with tumor size (R = 0.3957, p = 0.0049) and intratumoral levels of testosterone (R = 0.41, p = 0.0023) in LNCaP tumors grown in hormonally intact mice. We demonstrate tumoral expression of cholesterol uptake genes as well as the spectrum of steroidogenic enzymes necessary for androgen biosynthesis from cholesterol. Moreover, we show that circulating cholesterol levels are directly correlated with tumoral expression of CYP17A, the critical enzyme required for de novo synthesis of androgens from cholesterol (R = 0.4073, p = 0.025) Since hypercholesterolemia does not raise circulating androgen levels and the adrenal gland of the mouse synthesizes minimal androgens, this study provides evidence that hypercholesterolemia increases intratumoral de novo steroidogenesis. Our results are consistent with the hypothesis that cholesterol-fueled intratumoral androgen synthesis may accelerate the growth of prostate tumors, and suggest that treatment of CRPC may be optimized by inclusion of cholesterol reduction therapies in conjunction with therapies targeting androgen synthesis and the AR. |
| first_indexed | 2024-12-13T05:24:36Z |
| format | Article |
| id | doaj.art-a64edf3aa83645b8ad0255a8a57495ea |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T05:24:36Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-a64edf3aa83645b8ad0255a8a57495ea2022-12-21T23:58:14ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0171e3006210.1371/journal.pone.0030062Impact of circulating cholesterol levels on growth and intratumoral androgen concentration of prostate tumors.Elahe A MostaghelKeith R SolomonKristine PeltonMichael R FreemanR Bruce MontgomeryProstate cancer (PCa) is the second most common cancer in men. Androgen deprivation therapy (ADT) leads to tumor involution and reduction of tumor burden. However, tumors eventually reemerge that have overcome the absence of gonadal androgens, termed castration resistant PCa (CRPC). Theories underlying the development of CRPC include androgen receptor (AR) mutation allowing for promiscuous activation by non-androgens, AR amplification and overexpression leading to hypersensitivity to low androgen levels, and/or tumoral uptake and conversion of adrenally derived androgens. More recently it has been proposed that prostate tumor cells synthesize their own androgens through de novo steroidogenesis, which involves the step-wise synthesis of androgens from cholesterol. Using the in vivo LNCaP PCa xenograft model, previous data from our group demonstrated that a hypercholesterolemia diet potentiates prostatic tumor growth via induction of angiogenesis. Using this same model we now demonstrate that circulating cholesterol levels are significantly associated with tumor size (R = 0.3957, p = 0.0049) and intratumoral levels of testosterone (R = 0.41, p = 0.0023) in LNCaP tumors grown in hormonally intact mice. We demonstrate tumoral expression of cholesterol uptake genes as well as the spectrum of steroidogenic enzymes necessary for androgen biosynthesis from cholesterol. Moreover, we show that circulating cholesterol levels are directly correlated with tumoral expression of CYP17A, the critical enzyme required for de novo synthesis of androgens from cholesterol (R = 0.4073, p = 0.025) Since hypercholesterolemia does not raise circulating androgen levels and the adrenal gland of the mouse synthesizes minimal androgens, this study provides evidence that hypercholesterolemia increases intratumoral de novo steroidogenesis. Our results are consistent with the hypothesis that cholesterol-fueled intratumoral androgen synthesis may accelerate the growth of prostate tumors, and suggest that treatment of CRPC may be optimized by inclusion of cholesterol reduction therapies in conjunction with therapies targeting androgen synthesis and the AR.http://europepmc.org/articles/PMC3261168?pdf=render |
| spellingShingle | Elahe A Mostaghel Keith R Solomon Kristine Pelton Michael R Freeman R Bruce Montgomery Impact of circulating cholesterol levels on growth and intratumoral androgen concentration of prostate tumors. PLoS ONE |
| title | Impact of circulating cholesterol levels on growth and intratumoral androgen concentration of prostate tumors. |
| title_full | Impact of circulating cholesterol levels on growth and intratumoral androgen concentration of prostate tumors. |
| title_fullStr | Impact of circulating cholesterol levels on growth and intratumoral androgen concentration of prostate tumors. |
| title_full_unstemmed | Impact of circulating cholesterol levels on growth and intratumoral androgen concentration of prostate tumors. |
| title_short | Impact of circulating cholesterol levels on growth and intratumoral androgen concentration of prostate tumors. |
| title_sort | impact of circulating cholesterol levels on growth and intratumoral androgen concentration of prostate tumors |
| url | http://europepmc.org/articles/PMC3261168?pdf=render |
| work_keys_str_mv | AT elaheamostaghel impactofcirculatingcholesterollevelsongrowthandintratumoralandrogenconcentrationofprostatetumors AT keithrsolomon impactofcirculatingcholesterollevelsongrowthandintratumoralandrogenconcentrationofprostatetumors AT kristinepelton impactofcirculatingcholesterollevelsongrowthandintratumoralandrogenconcentrationofprostatetumors AT michaelrfreeman impactofcirculatingcholesterollevelsongrowthandintratumoralandrogenconcentrationofprostatetumors AT rbrucemontgomery impactofcirculatingcholesterollevelsongrowthandintratumoralandrogenconcentrationofprostatetumors |