Sanford-Burnham Science Blog
Prostate cancer cells expressing a mutant form of c-Myc that cannot be altered by PKCzeta (left) are more aggressive and more invasive than prostate cancer cells in which PKCzeta is able to keep tabs on c-Myc (right).
The enzyme PKCζ acts as a tumor suppressor by keeping the pro-tumor c-Myc gene in check, in both mice and humans.
Researchers have identified how an enzyme called PKCζ suppresses prostate tumor formation. The finding, which also describes a molecular chain of events that controls cell growth and metastasis, could lead to novel ways to control disease progression.
Cells proliferating in an intestinal tumor
Researchers discover that tumors lacking the protein PKCζ are good at surviving when nutrients are scarce—opening a new therapeutic avenue that targets cancer metabolism.
Cancer cells need food to survive and grow. They’re very good at getting it, too, even when nutrients are scarce. Many scientists have tried killing cancer cells by taking away their favorite food, a sugar called glucose. Unfortunately, this treatment approach not only fails to work, it backfires—glucose-starved tumors actually get more aggressive. In a study published January 31 in the journal Cell, researchers discovered that a protein called PKCζ is responsible for this paradox. The research suggests that glucose depletion therapies might work against tumors as long as the cancer cells are producing PKCζ.
PKCζ: critical regulator of tumor metabolism
According to this study, when PKCζ is missing from cancer cells, tumors are able to use alternative nutrients. What’s more, the lower the PKCζ levels, the more aggressive the tumor.
“We found an interesting correlation in colon cancers—if a patient’s tumor doesn’t produce PKCζ, he has a poorer prognosis than a similar patient with the protein. We looked specifically at colon cancer in this study, but it’s likely also true for other tumor types,” said Jorge Moscat, Ph.D., a professor at Sanford-Burnham. Moscat led the study in close collaboration with colleague Maria Diaz-Meco, Ph.D.
Sanford-Burnham Professors Jorge Moscat, Ph.D., and Maria Diaz-Meco, Ph.D. co-authored a study on p62's role in fat metabolism
Sanford-Burnham researchers show that protein p62 balances metabolism in fat tissue—making it an attractive target for anti-obesity therapies
In many cases, obesity is caused by more than just overeating and a lack of exercise. Something in the body goes haywire, causing it to store more fat and burn less energy. But what is it? Sanford-Burnham researchers have a new theory—a protein called p62. According to a study the team published December 21 in the Journal of Clinical Investigation, when p62 is missing in fat tissue, the body’s metabolic balance shifts—inhibiting “good” brown fat, while favoring “bad” white fat. These findings indicate that p62 might make a promising target for new therapies aimed at curbing obesity.
“Without p62 you’re making lots of fat but not burning energy, and the body thinks it needs to store energy,” said Jorge Moscat, Ph.D., Sanford-Burnham professor. “It’s a double whammy.” Moscat led the study with collaborators at Helmholtz Zentrum München in Germany and the University of Cincinnati.
Dr. John Reed speaks to the Sanford-Burnham community at his State of the Institute address.
Each January, John Reed, Sanford-Burnham’s CEO, reviews the accomplishments of the previous year in his State of the Institute address, which he presents to our community at both our Orlando and San Diego locations. This year, he reflected not just on 2011, but on the past decade. It was 10 years ago—in January 2002—that Reed was first named CEO. An accomplished scientist in his own right, Reed has led the Institute during a period of tremendous growth.
Dr. Maria Diaz-Meco (left), professor and senior author, and Dr. Angeles Duran, research assistant professor and one of the study’s first authors
In cancer, genes turn on and off at the wrong times, proteins aren’t folded properly, and cellular growth and proliferation get out of control. Even a cancer cell’s metabolism goes haywire, as it loses the ability to appropriately sense nutrients and use them to generate energy. One particular piece of cellular machinery that is known to malfunction in a number of cancers is a group of proteins called mTORC1. This master control center coordinates many cellular functions by sensing external signals such as nutrients and growth factors and telling cells how to respond.
Now, in a paper published October 7 in Molecular Cell, Sanford-Burnham scientists have identified a new member of the mTORC1 team—a protein called p62—that is crucial to the cell’s response to dietary amino acids. This finding provides new information about mTORC1 and its role in cellular metabolism in both normal cells and cancer cells. What’s more, it provides scientists with a new therapeutic target for cancers in which mTORC1 malfunctions.
Dr. Mihee Kim, new postdoc in Dr. Robert Oshima's lab
Editor’s note: We often hear how important it is to make a good first impression. We thought it would be interesting to learn about newcomers’ first impressions of Sanford-Burnham, so we interviewed some new employees who each play a different role at the Institute’s La Jolla campus.
One of our most recent employees, Dr. Mihee Kim, has been a postdoctoral associate in Dr. Robert Oshima’s lab since June of this year. From previous positions at Harvard and NIH, Mihee had experience both with stem cells and with proteins that bind to nucleic acids (such as DNA). She is combining those disciplines in the Oshima lab’s attempt to understand the role of the Ets2 transcription factor (a protein that controls the expression of other genes) in the behavior of cancer stem cells. Mihee had heard of Sanford-Burnham because a former Harvard colleague, Dr. Dieter Wolf, took a position as professor here in 2007. She had no preconceived impressions of the Institute, but has been pleased to learn that our claims of having a collaborative culture are not overstated. Being somewhat new to working with animal models, Mihee has already established interactions with postdocs in several Institute labs to develop a robust system for identifying intestinal stem cells. She has also found the imaging and flow cytometry shared services to be very effective resources for interaction and for providing both training and expert analysis.
Most amazing, she says, is the fact that, “people actually respond in a helpful way to e-mail requests for advice and reagents. I never had that experience before!”
Mihee is excited about the freedom she has been given by Dr. Oshima to explore multiple aspects of Ets2/cancer stem cell function according to her own curiosity and intuition.
Dr. Jorge Moscat and Dr. Maria Diaz-Meco
Fifty years ago, cancer biologists were convinced that understanding cancer metabolism would lead to a cure, until discoveries about cancer genetics shifted the research focus in other directions. But now the pendulum is swinging back, renewing interest in metabolism’s role in cancer.
Dr. Jorge Moscat and Dr. Maria Diaz-Meco, who both recently arrived at Sanford-Burnham from the University of Cincinnati, have been working together for more than twenty years to understand the mechanisms that allow cancer cells to grow at such a breakneck pace. Their investigations have led them to a network of proteins characterized by having PB1 domains. This network of proteins controls inflammation, how cells communicate with each other, and how they sense nutrients—all key drivers of cancer growth.
For example, the PB1-containing scaffold protein p62 regulates an enzyme called protein kinase C zeta (PKCZ), which is often missing in human cancers. PKCZ is a tumor suppressor that prevents inflammation and ensures that cells remain sensitive to nutrient levels. Cells without PKCZ get reprogrammed to endure food scarcity.
“If they lack this gene, they don’t care if glucose is unavailable,” says Dr. Moscat, “they just use other nutrients.”
