Gene may be good target for tough-to-kill prostate cancer cells

Sep 27, 2011 by Brian Wallheimer
Xiaoqi Liu believes Polo-like kinase 1, a protein important in cell duplication, could be a good target for treating late-stage prostate cancers. (Purdue Agricultural Communication photo/Tom Campbell)

Purdue University scientists believe they have found an effective target for killing late-stage, metastatic prostate cancer cells.

Xiaoqi Liu, an assistant professor of biochemistry and member of Purdue's Center for Cancer Research, and graduate student Shawn Liu are focusing on the function of a gene called Polo-like kinase (Plk1), a critical regulator of the cell cycle. Plk1 is also an oncogene, which tends to mutate and can cause cancer.

The researchers found that later-stage are missing Pten, a tumor-suppressor gene. The loss of Pten causes problems during cell division. Instead of the parent cell giving equal copies of DNA to two , those new cells receive disproportionate amounts, causing mutations.

"This turns out to be a major driving factor in future cancer," said Xiaoqi Liu, whose findings were published in the . "Without Pten, there is huge potential to become a cancer cell."

When Pten is diminished, the cells become stressed. To compensate, they increase production of Plk1, which causes rapid cell division.

"That's usually a hallmark of ," Xiaoqi Liu said.

This particular type of later-stage is troublesome because the cells do not respond to drugs aimed at stopping cell division and spread to other areas. When Pten is missing, Xiaoqi Liu said, those drugs actually increase the production of more Plk1.

To test the theory that Plk1 is a key to cancer formation, the researchers tested a Plk1 inhibitor called BI 2356 on both human and mice. In both tests, some cancer cells had Pten present while others had lost it.

In both cases, the cells without Pten responded to the drug.

"In later stages of prostate cancer, cells have lost Pten," Xiaoqi Liu said. "This means the Plk1 inhibitor can be a good drug for treatment of those tumors."

Xiaoqi Liu said tests also showed that BI 2536 could also be effective at low dosages, meaning side effects might be less severe.

Next, the researchers will try to replicate the findings in another mouse model. The National Institutes of Health funded the research.

Contributing to the research were: Timothy Ratliff, the Robert Wallace Miller Director of the Purdue Center for ; Stephen Konieczny, a Purdue professor of biological sciences; Bennett Elzey, a Purdue assistant research professor in comparative pathobiology; Bing Song, a Purdue graduate student in biological sciences; Liang Cheng, an Indiana University professor of pathology; and Nihal Ahmad, a University of Wisconsin professor of dermatology.

Explore further: Structure of sodium channels different than previously believed

More information: Polo-like Kinase 1 Facilitates Loss of pten-induced Prostate Cancer Formation, Journal of Biological Chemistry.

ABSTRACT
Loss of the tumor suppressor Pten (phosphatase and tensin homolog deleted on chromosome 10) is thought to mediate the majority of prostate cancers, but the molecular mechanism remains elusive. In this study, we demonstrate that Pten-depleted cells suffer from mitotic stress, and that nuclear function of Pten, but not its phosphastase activity, is required to reverse this stress phenotype. Further, depletion of Pten results in elevated expression of Polo-like kinase 1 (Plk1), a critical regulator of the cell cycle. We show that overexpression of Plk1 correlates with genetic inactivation of Pten during prostate neoplasia formation. Significantly, we find that elevated Plk1 is critical for Pten-depleted cells to adapt to mitotic stress for survival, and that re-introduction of wild-type Pten into Pten-null prostate cancer cells reduces the survival dependence on Plk1. We further show that Plk1 confers the tumorigenic competence of Pten-deleted prostate cancer cells in a mouse xenograft model. These findings identify a role of Plk1 in facilitating loss of Pten-induced prostate cancer formation, which suggests that Plk1 might be a promising target for prostate cancer patients with inactivating Pten mutations.

Related Stories

Preventing prostate cancer the complex way

Feb 03, 2009

(PhysOrg.com) -- Blocking a specific protein complex prevents the formation of tumors in mice genetically predisposed to develop prostate cancer, researchers at the Whitehead Institute for Biomedical Research ...

Anti-cancer effects of broccoli ingredient explained

Jul 13, 2010

Light has been cast on the interaction between broccoli consumption and reduced prostate cancer risk. Researchers writing in BioMed Central's open access journal Molecular Cancer have found that sulforaphane, a chemical found ...

Gene helps protect tumor suppressor in breast cancer

Apr 06, 2009

Scientists at The University of Texas M. D. Anderson Cancer Center have discovered a gene that protects PTEN, a major tumor-suppressor that is reduced but rarely mutated in about half of all breast cancers.

Recommended for you

Breakthrough points to new drugs from nature

Apr 16, 2014

Researchers at Griffith University's Eskitis Institute have developed a new technique for discovering natural compounds which could form the basis of novel therapeutic drugs.

World's first successful visualisation of key coenzyme

Apr 16, 2014

Japanese researchers have successfully developed the world's first imaging method for visualising the behaviour of nicotine-adenine dinucleotide derivative (NAD(P)H), a key coenzyme, inside cells. This feat ...

User comments : 0

More news stories

Making graphene in your kitchen

Graphene has been touted as a wonder material—the world's thinnest substance, but super-strong. Now scientists say it is so easy to make you could produce some in your kitchen.