Starving prostate cancer

Prostate cancers are hungry, growing cells. Now we know how to cut off their food supply thanks to research to be published later this month in Cancer Research—work funded by Movember and the Prostate Cancer Foundation of Australia

Researchers at the Centenary Institute in Sydney have discovered a potential future treatment for prostate cancer—through starving the tumour cells of an essential nutrient they need to grow rapidly.

Their work, with human cells grown in the lab, reveals targets for drugs that could slow the progress of early and late stage prostate cancer.

 

• Background information
• Citation and link to paper
• Images

Each year about 3300 Australian men die of prostate cancer. It’s Australia’s second worst cancer killer for men, matching the impact of breast cancer on women.

Current therapies for prostate cancer include surgical removal of the prostate, radiation, freezing the tumour or cutting off the supply of the hormone testosterone—but there are often side-effects including incontinence and impotence.

Growing cells need an essential nutrient, the amino acid called leucine, which is pumped into the cell by specialised proteins. And this could be prostate cancer’s weak link.

Dr Jeff Holst and his team at the Centenary Institute found in a study to be published in November’s Cancer Research that prostate cancer cells have more pumps than normal. This allows the cancer cells to take in more leucine and outgrow normal cells.

“This information allows us to target the pumps – and we’ve tried two routes. We found that we could disrupt the uptake of leucine firstly by reducing the amount of the protein pumps, and secondly by introducing a drug that competes with leucine. Both approaches slowed cancer growth, in essence ‘starving’ the cancer cells,” Jeff says.

First author Dr Qian Wang says by targeting different sets of pumps, the researchers were able to slow tumour growth in both the early and late stages of prostate cancer. “In some of the experiments, we were able to slow tumour growth by as much as 50 per cent. Our hope is that we could develop a treatment that slows the growth of the cancer so that it would not require surgical removal. If animal trials are successful over the next few years then clinical trials could start in as little as five years,” he says.

Jeff says one of the other spin-offs of the discovery is a better understanding of the links between prostate cancer and eating foods high in leucine. “Diets high in red meat and dairy are correlated with prostate cancer but still no one really understands why.  We have already begun examining whether these pumps can explain the links between diet and prostate cancer.”

“Given one in nine men in Australia may develop prostate cancer in their lifetime, this discovery could touch thousands of lives.”

The publication of the study comes just in time for Movember, a month-long charity drive in which thousands of people around the globe grow moustaches to raise money for men’s health issues including prostate cancer.

“This fundamental research tells us more about how prostate and other cancers grow, and will open the way for new treatments in the long term,” says Movember chairman Paul Villanti.

“Movember is now one of the largest non-government global funders of prostate cancer research. We strongly support innovative targeted research that leads to significantly improved clinical tests and treatments to reduce the burden of prostate cancer.  It’s great to see the progress that Dr Holst and his team have made with the support of a Movember Young Investigator grant.

PCFA and Movember have been working together since 2004 to reduce the impact of prostate cancer on Australian men and their loved ones.

PCFA CEO Dr Anthony Lowe says research that has the potential to reduce the impact of prostate cancer on those who are diagnosed is a huge priority for the PCFA’s grants program. “We commend the team at the Centenary Institute on the remarkable progress they are making in this regard,” he says.

“This is part of a body of work that is investigating the very nature of cancer and opening up new avenues for cancer treatment,” says Centenary Institute executive director Professor Mathew Vadas.

• For interviews contact: Jeff Holst +61 401 081 974 or +61 2 9565 6172
• For hi-res images, backgrounder, paper and full release go to: http://www.scienceinpublic.com.au/centenary

Or call Andrew Wight on +61 3 9398 1416, +61 422 982 829

• For more information on Movember: http://au.movember.com
• For more information on the Prostate Cancer Foundation of Australia: http://www.prostate.org.au

Prostate cancer is the most common cancer in Australian men and is the second most common cause of cancer deaths in men (after lung cancer).  Generally at the early and potentially curable stage, prostate cancer does not have obvious symptoms. This makes it different from other benign prostate disorders, which may result in urinary symptoms. Men aged 50 and over should talk to their doctor about prostate cancer and if they decide to be tested, to do so annually. If there is a family history of prostate cancer; men should talk to their doctor from the age of 40.

Source: Prostate Cancer Foundation of Australia For more on prostate cancer diagnosis, treatment and support: http://www.prostate.org.au

Citation

Cancer Res. 2011 Oct 17. [Epub ahead of print]

Androgen receptor and nutrient signalling pathways coordinate the demand for increased amino acid transport during prostate cancer progression.

Qian Wang1,2, Charles G. Bailey2,3, Cynthia Ng2, Jessamy Tiffen1,2, Annora Thoeng2, Vineet

Minhas1,2, Melanie L. Lehman4, Stephen C. Hendy4, Grant Buchanan5, Colleen C. Nelson4,6,

John E.J. Rasko2,3,7 and Jeff Holst1,2,3.

Abstract

L-type amino acid transporters such as LAT1 and LAT3 mediate uptake of essential amino acids such as leucine. Here we report that prostate cancer cells coordinate the expression of LAT1 and LAT3, thereby maintaining sufficient levels of leucine for mTORC1 signalling and cell growth.

We show that inhibition of LAT function leads to decreased cell growth and mTORC1 signalling in prostate cancer cells. These cells maintain amino acid influx via androgen receptor regulation of LAT3 expression, and ATF4 regulation of LAT1 expression after amino acid deprivation.

These responses are intact in primary prostate cancer, as indicated by high levels of LAT3 in primary disease, and an increase in LAT1 following hormone ablation and in metastatic lesions.

These data show that prostate cancer cells respond to the demand for increased amino acids through an integrated pathway, leading to increased amino acid transporter expression and cell growth.

Authors’ Affiliation:

1Origins of Cancer Laboratory and 2Gene & Stem Cell Therapy Program,

Centenary Institute, Camperdown, Australia; 3Sydney Medical School, University of Sydney,

Australia; 4Vancouver Prostate Centre, Department of Urologic Sciences, University of British

Columbia, Vancouver, Canada; 5Molecular Ageing Laboratory, University of Adelaide;

6Australian Prostate Cancer Research Centre-Queensland, Queensland University of Technology,

Australia; 7Cell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown, Australia.

Full paper at: http://bit.ly/uTC32L

About Jeff Holst

Dr Jeff Holst heads the Origins of Cancer laboratory at Centenary Institute and is associate faculty there. Jeff’s lab is focused on increasing our understanding of the metabolic requirements of tumours, which may lead to new treatments.

About the Centenary Institute:

Centenary Institute’s dedicated scientists conduct fundamental research to understand the work of the body’s genes, cells and proteins.  Centenary’s affiliation with the RPA Hospital and the University of Sydney means they can translate directly the discoveries in the lab to prevent diseases that affect so many of us.

More at: http://www.centenary.org.au/

About Prostate Cancer Foundation of Australia and Movember

The Prostate Cancer Foundation of Australia (PCFA) have been partners of Movember since 2004 and together are working towards a shared goal of reducing the impact of prostate cancer on Australian men and their loved ones.

Together, Movember and the PCFA are dedicated to funding Australian research into the cause, diagnosis, prevention and treatment of prostate cancer; providing information, support and advocacy to those affected by prostate cancer and raising community awareness about prostate cancer.  PCFA receives limited government funding, instead relying on the generosity of the Movember community, and partners like Movember to provide and grow its vital services across Australia.

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