Metabolic enzyme stops progression of most common type of kidney cancer

July 20, 2014

PHILADELPHIA -- In an analysis of small molecules called metabolites used by the body to make fuel in normal and cancerous cells in human kidney tissue, a research team from the Perelman School of Medicine at the University of Pennsylvania identified an enzyme key to applying the brakes on tumor growth. The team found that an enzyme called FBP1 - essential for regulating metabolism - binds to a transcription factor in the nucleus of certain kidney cells and restrains energy production in the cell body. What's more, they determined that this enzyme is missing from all kidney tumor tissue analyzed. These tumor cells without FBP1 produce energy at a much faster rate than their non-cancer cell counterparts. When FBP1 is working properly, out-of-control cell growth is kept in check.

The new study, published online this week in Nature, was led by Celeste Simon, PhD, a professor of Cell and Developmental Biology and the scientific director for the Abramson Family Cancer Research Institute at Penn.

Clear cell renal cell carcinoma (ccRCC), the most frequent form of kidney cancer, is characterized by elevated glycogen (a form of carbohydrate) and fat deposits in affected kidney cells. This over-storage of lipids causes large clear droplets to accumulate, hence the cancer's name.

In the last decade, ccRCCs have been on the rise worldwide. However, if tumors are removed early, a patient's prognosis for five-year survival is relatively good. If expression of the FBP1 gene is lost, patients have a worse prognosis.

"This study is the first stop in this line of research for coming up with a personalized approach for people with clear cell renal cell carcinoma-related mutations," says Simon, also an investigator with the Howard Hughes Medical Institute.

A Series of Faulty Reactions

The aberrant storage of lipid in ccRCC results from a faulty series of biochemical reactions. These reactions, called the Kreb's cycle, generate energy from carbohydrates, fats, and proteins in the form of ATP. However, the Kreb's cycle is hyperactive in ccRCC, resulting in enhanced lipid production. Renal cancer cells are associated with changes in two important intracellular proteins: elevated expression of hypoxia inducible factors (HIFs) and mutations in the von Hippel-Lindau (VHL) encoded protein, pVHL. In fact, mutations in pVHL occur in 90 percent of ccRCC tumors. pVHL regulates HIFs, which in turn affect activity of the Kreb's cycle.

Although much is already known about metabolic pathways and their role in cancer, there are still important questions to be answered. For example, kidney-specific VHL deletion in mice does not elicit clear cell-specific tumor formation, suggesting that additional mechanisms are at play. Toward answering that hunch, recent large-scale sequencing analyses have revealed the loss of several epigenetic enzymes in certain types of ccRCCs, suggesting that changes within the nucleus also account for kidney tumor progression.

To complement genetic studies revealing a role for epigenetic enzymes, the team evaluated metabolic enzymes in the 600-plus tumors they analyzed. The expression of FBP1 was lost in all kidney cancer tissue samples examined. They found FBP1 protein in the cytoplasm of normal cells, where it would be expected to be active in glucose metabolism. But, they also found FBP1 in the nucleus of these normal cells, where it binds to HIF to modulate its effects on tumor growth. In cells without FBPI, the team observed the Warburg effect - a phenomenon in which malignant, rapidly growing tumor cells go into overdrive, producing energy up to 200 times faster than their non-cancer-cell counterparts.

This unique dual function of FBP1 explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously identified tumor suppressors that are not consistently inhibited in all tumors. "And since FBP1 activity is also lost in liver cancer, which is quite prevalent, FBP1 depletion may be generally applicable to a number of human cancers," notes Simon.

Next steps, according to the researchers, will be to identify other metabolic pathways to target, measure the abundance of metabolites in kidney and liver cancer cells to determine FBP1's role in each, and develop a better mouse model for preclinical studies.
-end-
Co-authors are Bo Li, Bo Qiu, David S.M. Lee, Zandra E. Walton, Joshua D. Ochocki, Lijoy K. Mathew, Anthony Mancuso, Terence P.F. Gade, and Brian Keith, all from Penn, as well as Itzhak Nissim, from The Children's Hospital of Philadelphia.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2013 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2013, Penn Medicine provided $814 million to benefit our community.

University of Pennsylvania School of Medicine

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.