Researchers identify 'Achilles' heel' of PTEN that helps drive prostate cancer progression

February 13, 2017, Cold Spring Harbor Laboratory
Postdoctoral researchers Muhan Chen, Dawid G. Nowak and others in the Trotman lab at CSHL may have solved a mystery about prostate cancer: why some patients appear to have low levels of the powerful tumor-suppressing protein PTEN and yet have no mutations in the gene that encodes the protein. The answer is implied in this image. In a sample of mouse prostate tissue on the way to becoming cancerous, they show one area in which PTEN protein levels are high (Area 1, yellow dashes) and a nearby area (Area 2, red dashes) where they are low. Where PTEN is low, so are levels of a protein called Importin 11 (Ipo11); where PTEN is abundant, so too is Ipo11. Ipo11 saves PTEN proteins marked for destruction by carrying them into the cell nucleus, perhaps in this way forming a "reservoir" and saving PTEN for future use in the battle against the emerging tumor. When Ipo11 is missing, cancer progression is promoted. Credit: Trotman Lab, CSHL

Researchers at Cold Spring Harbor Laboratory (CSHL) have discovered that a protein called Importin-11 protects the anti-cancer protein PTEN from destruction by transporting it into the cell nucleus. A study they publish today in The Journal of Cell Biology suggests that the loss of Importin-11 may destabilize PTEN, leading to the development of lung, prostate, and other cancers.

PTEN prevents tumor cells from growing uncontrollably, and mutations in the gene encoding this are commonly found in many different types of cancer. Some patients, however, show low levels of the PTEN protein even though their PTEN genes are normal. CSHL Associate Professor Lloyd Trotman and colleagues discovered that this may be due to defects in Importin-11, which transports PTEN into the nucleus, sheltering PTEN from proteins in the cell's cytoplasm that would otherwise target it for degradation.

Several cytoplasmic proteins—NEDD4-1, NDFIP1, and UBE2E1—combine to tag PTEN with the small molecule ubiquitin. PTEN tagged with multiple ubiquitin molecules can then be recognized and destroyed by the cell's protein degradation machinery. Trotman and colleagues found that Importin-11 protects PTEN from degradation by escorting not only PTEN but also UBE2E1 into the nucleus, thereby breaking up the cytoplasmic ubiquitination apparatus.

Mice lacking Importin-11 showed lower levels of PTEN protein and developed lung adenocarcinomas and prostate neoplasias. Mutations in the gene encoding Importin-11 have been identified in human cancers, and Trotman and colleagues found that tumors from lacking Importin-11 tended to show low PTEN levels as well. The researchers estimate that loss of Importin-11 may account for the loss of PTEN in approximately one-third of lung cancer patients lacking this key anti-cancer protein.

In prostate cancer, loss of Importin-11 predicted disease relapse and metastasis in patients who had had their prostate removed. "We think that the degradation of PTEN after loss or impairment of Importin-11 is a very effective driver of human ," says Trotman. "Our results suggest that Importin-11 is the 'Achilles' heel' of the ubiquitination system that maintains the correct levels of PTEN inside cells."

Cross sections of prostate tissue in healthy mice (top row) and mice in which cancer is beginning to develop (bottom row). Healthy tissue shows regular structures and empty spaces (white in the far left image) called lumen. Cancerous tissue is less organized, and is more densely populated with cells, which are proliferating abnormally. Insets show consistently that when Ipo11 is abundant, so is PTEN tumor-suppressing protein; when PTEN levels are low, so is the protein Importin 11 (Ipo11). Its presence of absence may be a useful diagnostic and therapeutic marker in prostate biopsies. Credit: Trotman lab, CSHL

Explore further: Researchers identify 'synthetic essentiality' as novel approach for locating cancer therapy targets

More information: "The Nuclear Transport Receptor Importin-11 is a Tumor Suppressor that Maintains PTEN Protein," appears in The Journal of Cell Biology, jcb.rupress.org/cgi/doi/10.1083/jcb.201604025

Related Stories

Researchers identify 'synthetic essentiality' as novel approach for locating cancer therapy targets

February 6, 2017
A new method has been found for identifying therapeutic targets in cancers lacking specific key tumor suppressor genes. The process, which located a genetic site for the most common form of prostate cancer, has potential ...

Rare childhood disease linked to major cancer gene

December 1, 2016
A team of researchers led by a University of Rhode Island scientist has discovered an important molecular link between a rare childhood genetic disease, Fanconi anemia, and a major cancer gene called PTEN. The discovery improves ...

New research sheds light on gene destruction linked to aggressive prostate cancer

January 26, 2012
Researchers at Queen's University in Kingston, Canada have identified a possible cause for the loss of a tumour suppressor gene (known as PTEN) that can lead to the development of more aggressive forms of prostate cancer.

COUP-TFII sparks prostate cancer progression

November 28, 2012
Prostate cancer presents a dilemma for patients and the physicians who treat them. Which cancers are essentially indolent and present no risk and which are life threatening? Which can be watched and which need aggressive ...

Recommended for you

Stem cell vaccine immunizes lab mice against multiple cancers

February 15, 2018
Stanford University researchers report that injecting mice with inactivated induced pluripotent stem cells (iPSCs) launched a strong immune response against breast, lung, and skin cancers. The vaccine also prevented relapses ...

Induced pluripotent stem cells could serve as cancer vaccine, researchers say

February 15, 2018
Induced pluripotent stem cells, or iPS cells, are a keystone of regenerative medicine. Outside the body, they can be coaxed to become many different types of cells and tissues that can help repair damage due to trauma or ...

Team paves the way to the use of immunotherapy to treat aggressive colon tumors

February 15, 2018
In a short space of time, immunotherapy against cancer cells has become a powerful approach to treat cancers such as melanoma and lung cancer. However, to date, most colon tumours appeared to be unresponsive to this kind ...

Can our genes help predict how women respond to ovarian cancer treatment?

February 15, 2018
Research has identified gene variants that play a significant role in how women with ovarian cancer process chemotherapy.

First comparison of common breast cancer tests finds varied accuracy of predictions

February 15, 2018
Commercially-available prognostic breast cancer tests show significant variation in their abilities to predict disease recurrence, according to a study led by Queen Mary University of London of nearly 800 postmenopausal women.

Catching up to brain cancer: Researchers develop accurate model of how aggressive cancer cells move and spread

February 15, 2018
A brief chat at a Faculty Senate meeting put two University of Delaware researchers onto an idea that could be of great value to cancer researchers.

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.