The androgen receptor in prostate cancer cells can activate different sets of genes depending on whether it binds with an androgen hormone or an antiandrogen drug, according to a new study led by researchers at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James).
The study found that when androgen receptor (AR) binds with testosterone or dihydrotestosterone, the activated receptor binds, as expected, to segments of DNA called androgen response elements.
But when the receptor binds with either of two antiandrogenic drugs, bicalutamide or enzalutamide, it then binds to different DNA sequences and activates entirely different sets of genes, including cancer-promoting oncogenes.
The researchers called these newly discovered AR binding sites on DNA "antiandrogen response elements" and showed that they activate genes that might enable tumor progression during antiandrogen treatment.
The findings, reported in EMBO Journal, suggest that the treatment of prostate cancer with antiandrogenic drugs should include agents that target antiandrogen-regulated oncogenes.
"The discovery of antiandrogen response elements was completely unexpected," says principal investigator and OSUCCC - James researcher Qianben Wang, PhD, associate professor of molecular virology, immunology and medical genetics.
He noted that antiandrogen agents are known to work by competing with androgens to bind to AR, thus inhibiting androgen-induced gene expression.
"But we found that antiandrogens can also trigger AR to bind to DNA sequences that are distinctly different from androgen response elements, and thus regulate genes relevant to prostate cancer development," Wang says.
Prostate cancer is the most frequently diagnosed cancer in men. An estimated 220,800 new cases are expected in the United States in 2015, along with 27,540 deaths from the disease.
In advanced hormone-dependent prostate cancer, hormone-activated androgen receptor drives tumor growth. Antiandrogen drugs such as bicalutamide and enzalutamide bind with androgen receptor to prevent them from activating genes that drive cancer progression.
Although initially responsive to these drugs, prostate cancer ultimately progresses to a lethal, treatment-resistant state that is currently incurable. "Our findings suggest that improved antiandrogen therapies could be achieved by simultaneously targeting antiandrogen-regulated oncogenes," Wang says.
Wang and first author Zhong Chen, a research scientist at the OSUCCC - James, developed most of the study's scientific concepts. They and their colleagues conducted the research using prostate cancer cell lines and samples of human prostate tumors and adjacent normal tissues.
Key findings include:
- The team precisely categorized androgen response elements into four distinct classes;
- Bicalutamide and enzalutamide enhanced the binding of AR to a group of genomic locations that lack androgen response elements;
- The oncogene CPEB4 showed a significant increase in expression in prostate cancer cells treated with enzalutamide compared with untreated and androgen-treated cells;
- Silencing CPEB4 enhanced the ability of enzalutamide to inhibit the proliferation of prostate cancer cells.
"Overall, we believe we've discovered a general mechanism for ligand-specific gene expression by certain ligand-dependent receptors," Wang says.
Explore further: Study identifies a key cellular pathway in prostate cancer
More information: EMBO Journal, http://ift.tt/1q9dxEm j.201490306/abstract
Medical Xpress on facebook
Related Stories
Study identifies a key cellular pathway in prostate cancer
Feb 10, 2014
Mayo Clinic researchers have shed light on a new mechanism by which prostate cancer develops in men. Central to development of nearly all prostate cancer cases are malfunctions in the androgen receptor—the cellular component ...
Three San Antonio studies target androgen in breast cancer
Dec 11, 2014
Three studies presented by University of Colorado Cancer Center researchers at the San Antonio Breast Cancer Symposium 2014 demonstrate the effects of blocking androgen receptors in breast cancer. One shows that, counterintuitively, ...
New medication treats drug-resistant prostate cancer in the laboratory
Jun 17, 2013
A new drug called pyrvinium pamoate inhibits aggressive forms of prostate cancer that are resistant to standard drugs, according to a study conducted in an animal model. The results will be presented Monday at The Endocrine ...
Possible new weapon found for fighting some types of breast cancer
Jun 23, 2014
Researchers believe they have discovered one reason why some women with estrogen receptor-positive breast cancer may respond poorly or only temporarily to estrogen-blocking drugs such as tamoxifen. Results of a new study, ...
Study identifies new prostate cancer drug target
Feb 06, 2012
Research led by Wanguo Liu, PhD, Associate Professor of Genetics at LSU Health Sciences Center New Orleans, has identified a new protein critical to the development and growth of prostate cancer. The findings are published ...
Recommended for you
Targeted MRI / ultrasound beats standard biopsy to detect high-risk prostate cancer
1 hour ago
Targeted biopsy using new fusion technology that combines magnetic resonance imaging (MRI) with ultrasound is more effective than standard biopsy in detecting high-risk prostate cancer, according to a large-scale study published ...
Researchers find potential anti-cancer use for anti-epilepsy drug
2 hours ago
Scientists at the University of York have discovered that a drug used widely to combat epilepsy has the potential to reduce the growth and spread of breast cancer.
Inherited gene variation helps explain drug toxicity in patients of East Asian ancestry
4 hours ago
About 10 percent of young leukemia patients of East Asian ancestry inherit a gene variation that is associated with reduced tolerance of a drug that is indispensable for curing acute lymphoblastic leukemia (ALL), the most ...
Inhibiting CDK6 prevents leukemic relapse
4 hours ago
Despite enormous progress in cancer therapy, many patients still relapse because their treatment addresses the symptoms of the disease rather than the cause, the so-called stem cells. Work in the group of ...
Metabolic process of the liver implicated in the spread of colorectal cancer
5 hours ago
Colorectal cancer is a cancer on the move: about 50 percent of patients with the disease see their cancer spread, typically to the liver. By identifying genes that become activated in cancer cells that successfully travel—metastasize—to ...
Smoking may increase risks for patients being treated for prostate cancer
12 hours ago
Among patients with prostate cancer, those who smoke have increased risks of experiencing side effects from treatment and of developing future cancer recurrences, or even dying from prostate cancer. The findings, which are ...
User comments
Please sign in to add a comment. Registration is free, and takes less than a minute. Read more
Click here to reset your password.
Sign in to get notified via email when new comments are made.
© Medical Xpress 2011-2014, Science X network
The androgen receptor in prostate cancer cells can activate different sets of genes depending on whether it binds with an androgen hormone or an antiandrogen drug, according to a new study led by researchers at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James).
The study found that when androgen receptor (AR) binds with testosterone or dihydrotestosterone, the activated receptor binds, as expected, to segments of DNA called androgen response elements.
But when the receptor binds with either of two antiandrogenic drugs, bicalutamide or enzalutamide, it then binds to different DNA sequences and activates entirely different sets of genes, including cancer-promoting oncogenes.
The researchers called these newly discovered AR binding sites on DNA "antiandrogen response elements" and showed that they activate genes that might enable tumor progression during antiandrogen treatment.
The findings, reported in EMBO Journal, suggest that the treatment of prostate cancer with antiandrogenic drugs should include agents that target antiandrogen-regulated oncogenes.
"The discovery of antiandrogen response elements was completely unexpected," says principal investigator and OSUCCC - James researcher Qianben Wang, PhD, associate professor of molecular virology, immunology and medical genetics.
He noted that antiandrogen agents are known to work by competing with androgens to bind to AR, thus inhibiting androgen-induced gene expression.
"But we found that antiandrogens can also trigger AR to bind to DNA sequences that are distinctly different from androgen response elements, and thus regulate genes relevant to prostate cancer development," Wang says.
Prostate cancer is the most frequently diagnosed cancer in men. An estimated 220,800 new cases are expected in the United States in 2015, along with 27,540 deaths from the disease.
In advanced hormone-dependent prostate cancer, hormone-activated androgen receptor drives tumor growth. Antiandrogen drugs such as bicalutamide and enzalutamide bind with androgen receptor to prevent them from activating genes that drive cancer progression.
Although initially responsive to these drugs, prostate cancer ultimately progresses to a lethal, treatment-resistant state that is currently incurable. "Our findings suggest that improved antiandrogen therapies could be achieved by simultaneously targeting antiandrogen-regulated oncogenes," Wang says.
Wang and first author Zhong Chen, a research scientist at the OSUCCC - James, developed most of the study's scientific concepts. They and their colleagues conducted the research using prostate cancer cell lines and samples of human prostate tumors and adjacent normal tissues.
Key findings include:
- The team precisely categorized androgen response elements into four distinct classes;
- Bicalutamide and enzalutamide enhanced the binding of AR to a group of genomic locations that lack androgen response elements;
- The oncogene CPEB4 showed a significant increase in expression in prostate cancer cells treated with enzalutamide compared with untreated and androgen-treated cells;
- Silencing CPEB4 enhanced the ability of enzalutamide to inhibit the proliferation of prostate cancer cells.
"Overall, we believe we've discovered a general mechanism for ligand-specific gene expression by certain ligand-dependent receptors," Wang says.
Explore further: Study identifies a key cellular pathway in prostate cancer
More information: EMBO Journal, http://ift.tt/1q9dxEm j.201490306/abstract
Medical Xpress on facebook
Related Stories
Study identifies a key cellular pathway in prostate cancer
Feb 10, 2014
Mayo Clinic researchers have shed light on a new mechanism by which prostate cancer develops in men. Central to development of nearly all prostate cancer cases are malfunctions in the androgen receptor—the cellular component ...
Three San Antonio studies target androgen in breast cancer
Dec 11, 2014
Three studies presented by University of Colorado Cancer Center researchers at the San Antonio Breast Cancer Symposium 2014 demonstrate the effects of blocking androgen receptors in breast cancer. One shows that, counterintuitively, ...
New medication treats drug-resistant prostate cancer in the laboratory
Jun 17, 2013
A new drug called pyrvinium pamoate inhibits aggressive forms of prostate cancer that are resistant to standard drugs, according to a study conducted in an animal model. The results will be presented Monday at The Endocrine ...
Possible new weapon found for fighting some types of breast cancer
Jun 23, 2014
Researchers believe they have discovered one reason why some women with estrogen receptor-positive breast cancer may respond poorly or only temporarily to estrogen-blocking drugs such as tamoxifen. Results of a new study, ...
Study identifies new prostate cancer drug target
Feb 06, 2012
Research led by Wanguo Liu, PhD, Associate Professor of Genetics at LSU Health Sciences Center New Orleans, has identified a new protein critical to the development and growth of prostate cancer. The findings are published ...
Recommended for you
Targeted MRI / ultrasound beats standard biopsy to detect high-risk prostate cancer
1 hour ago
Targeted biopsy using new fusion technology that combines magnetic resonance imaging (MRI) with ultrasound is more effective than standard biopsy in detecting high-risk prostate cancer, according to a large-scale study published ...
Researchers find potential anti-cancer use for anti-epilepsy drug
2 hours ago
Scientists at the University of York have discovered that a drug used widely to combat epilepsy has the potential to reduce the growth and spread of breast cancer.
Inherited gene variation helps explain drug toxicity in patients of East Asian ancestry
4 hours ago
About 10 percent of young leukemia patients of East Asian ancestry inherit a gene variation that is associated with reduced tolerance of a drug that is indispensable for curing acute lymphoblastic leukemia (ALL), the most ...
Inhibiting CDK6 prevents leukemic relapse
4 hours ago
Despite enormous progress in cancer therapy, many patients still relapse because their treatment addresses the symptoms of the disease rather than the cause, the so-called stem cells. Work in the group of ...
Metabolic process of the liver implicated in the spread of colorectal cancer
5 hours ago
Colorectal cancer is a cancer on the move: about 50 percent of patients with the disease see their cancer spread, typically to the liver. By identifying genes that become activated in cancer cells that successfully travel—metastasize—to ...
Smoking may increase risks for patients being treated for prostate cancer
12 hours ago
Among patients with prostate cancer, those who smoke have increased risks of experiencing side effects from treatment and of developing future cancer recurrences, or even dying from prostate cancer. The findings, which are ...
User comments
Please sign in to add a comment. Registration is free, and takes less than a minute. Read more
Click here
to reset your password.
Sign in to get notified via email when new comments are made.
© Medical Xpress 2011-2014, Science X network
0 comments:
Post a Comment