How some prostate tumors resist treatment—and how it might be fixed

March 18, 2013, Sanford-Burnham Medical Research Institute
Siah2 levels (brown staining) are high in human castration-resistant prostate cancer (left), as compared to benign prostate growths (right). Credit: Sanford-Burnham Medical Research Institute

Hormonal therapies can help control advanced prostate cancer for a time. However, for most men, at some point their prostate cancer eventually stops responding to further hormonal treatment. This stage of the disease is called androgen-insensitive or castration-resistant prostate cancer. In a study published March 18 in Cancer Cell, a team led by researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) found a mechanism at play in androgen-insensitive cells that enables them to survive treatment. They discovered that a protein called Siah2 keeps a portion of androgen receptors constantly active in these prostate cancer cells. Androgen receptors—sensors that receive and respond to the hormone androgen—play a critical role in prostate cancer development and progression.

Based on this new information, Siah2 could make a promising biomarker for tracking a prostate cancer patient's response to therapy. Inhibiting Siah2's interaction with the complex might also provide a new method for re-sensitizing castration-resistant to hormone therapy.

Siah2 removes the brake on androgen receptors

"Prostate tumors become castration-resistant by using diverse ways to modify androgen receptor to become constantly active. In this study, we demonstrate how this happens through a previously unknown mechanism orchestrated by Siah2. Surprisingly, it turns out that only a fraction of all androgen receptors are altered in castration-resistant tumors," said Ze'ev Ronai, Ph.D., associate director of Sanford-Burnham's -designated Cancer Center, scientific director of the Institute's La Jolla campus, and senior author of the study.

Normally, androgen receptors are kept in check by an inhibitor called NCOR1. This study revealed that, in castration-resistant prostate tumors, Siah2 tags the NCRO1-androgen receptor complex for degradation. That removes the brake, allowing the recycling of inactive androgen receptor to active status. As a result, produce more active androgen receptors, which render them resistant to hormone therapy.

Clinical relevance

Ronai and colleagues wondered if Siah2 plays the same role in real-life castration-resistant prostate cancer as they had observed in the lab. Using samples provided by collaborators at the Vancouver Prostate Centre at the University of British Columbia, the team determined that human castration-resistant prostate tumors have abnormally high levels of Siah2 and select androgen receptor targets. This finding underscores the clinical significance of the castration-resistance mechanism they uncovered.

Ronai and his team also looked at what happens when they inhibit Siah2. To do this, they used three different animal models. In each case, inhibiting Siah2 restored prostate tumors' sensitivity to hormone therapy. With Siah2 out of the picture, prostate tumors regressed during hormone therapy.

"We see Siah2 not only as a biomarker—a way to track the development and progression of castration-resistance—but also as a potential therapeutic target for ," explained Jianfei Qi, Ph.D., staff scientist in Ronai's lab and first author of the paper.

Explore further: Targeted cancer therapy kills prostate tumor cells

Related Stories

Targeted cancer therapy kills prostate tumor cells

June 6, 2011
A new targeted therapy for prostate cancer halts tumor growth in animals with advanced prostate cancer that is resistant to hormone therapy, a new study finds. The results will be presented Saturday at The Endocrine Society's ...

Study identifies new prostate cancer drug target

February 6, 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 ...

Curry spice component may help slow prostate tumor growth

February 10, 2012
Curcumin, an active component of the Indian curry spice turmeric, may help slow down tumor growth in castration-resistant prostate cancer patients on androgen deprivation therapy (ADT), a study from researchers at Jefferson's ...

Researchers find new culprit in castration-resistant prostate cancer

December 13, 2012
Scientists at Dana-Farber Cancer Institute have discovered a molecular switch that enables advanced prostate cancers to spread without stimulation by male hormones, which normally are needed to spur the cancer's growth. They ...

Recommended for you

How cancer metastasis happens: Researchers reveal a key mechanism

January 18, 2018
Cancer metastasis, the migration of cells from a primary tumor to form distant tumors in the body, can be triggered by a chronic leakage of DNA within tumor cells, according to a team led by Weill Cornell Medicine and Memorial ...

Modular gene enhancer promotes leukemia and regulates effectiveness of chemotherapy

January 18, 2018
Every day, billions of new blood cells are generated in the bone marrow. The gene Myc is known to play an important role in this process, and is also known to play a role in cancer. Scientists from the German Cancer Research ...

These foods may up your odds for colon cancer

January 18, 2018
(HealthDay)—Chowing down on red meat, white bread and sugar-laden drinks might increase your long-term risk of colon cancer, a new study suggests.

The pill lowers ovarian cancer risk, even for smokers

January 18, 2018
(HealthDay)—It's known that use of the birth control pill is tied to lower odds for ovarian cancer, but new research shows the benefit extends to smokers or women who are obese.

Researchers develop swallowable test to detect pre-cancerous Barrett's esophagus

January 17, 2018
Investigators at Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center have developed a simple, swallowable test for early detection of Barrett's esophagus that offers promise ...

Scientists zoom in to watch DNA code being read

January 17, 2018
Scientists have unveiled incredible images of how the DNA code is read and interpreted—revealing new detail about one of the fundamental processes of life.

0 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.