Study offers new approach to starve p53 deficient tumors

May 3, 2018, Sanford-Burnham Prebys Medical Discovery Institute
Brooke Emerling, Ph.D., is an Assistant Professor in Cancer Metabolism and Signaling Networks at Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California. Credit: Sanford Burnham Prebys Medical Discovery Institute

One major hallmark of cancer cells is their ability to adapt to stressful conditions such as nutrient deprivation. Rapidly growing tumor cells must compete for the ever-diminishing supply of nutrients in the surrounding environment to survive and proliferate. Targeting these adaptive mechanisms represents a promising approach for cancer therapeutics.

Sanford Prebys Medical Discovery Institute (SBP) researchers recently discovered an alternative metabolic pathway that might be used by to survive nutrient deprivation. As reported May 3 in the journal Molecular Cell, two proteins belonging to the PI5P4K family of enzymes— PI5P4Kα and PI5P4Kβ —are critical for a process called , which provides nutrients to starving cells by recycling cellular compartments. According to the authors, targeting these proteins to disrupt autophagy in cancer cells is an exciting therapeutic strategy that could minimize toxicity.

"The importance of this alternative pathway has been obscure since the discovery of these enzymes by the Lewis Cantley laboratory 20 years ago," says senior study author Brooke Emerling, Ph.D., assistant professor of the Cancer Metabolism and Signaling Networks Program at SBP. "Our study identifies a novel regulatory step in the process of autophagy and sheds light on the anti-cancer potential of PI5P4K inihibitors."

Surviving stress

Cells that are deprived of nutrients can maintain sufficient energy levels by degrading and recycling unnecessary or dysfunctional cellular components. This survival mechanism, known as autophagy, also plays key roles in a variety of processes such as development and aging, and is often perturbed in various diseases including neurodegenerative disorders, skeletal muscle myopathies, heart disease, liver disease and cancer.

During autophagy, cellular components such as abnormal molecules or damaged organelles are first sequestered within vesicles known as autophagosomes. These vesicles then fuse with organelles called lysosomes, which contain enzymes that break down various molecules. Even though tight control of autophagy is key to survival, relatively little is known about the signaling molecules that regulate this essential process.

In the new study, Emerling and Lewis Cantley, Ph.D., of Weill Cornell Medical College discovered that the PI5P4K family of enzymes, whose biological functions were previously unclear, plays a critical role in autophagy during times of metabolic stress. Deletion of the genes encoding the two most active enzymes in this pathway, Pip4k2a and Pip4k2b, in the liver of mice caused an accumulation of lipid droplets and autophagic vesicles during fasting. Similar changes were observed in nutrient-starved worms lacking the PI5P4K ortholog.

Additional experiments revealed what caused these autophagy defects. Nutrient-starved cells lacking Pip4k2a, Pip4k2b, and the tumor suppressor protein p53 showed evidence that autophagosomes could not successfully fuse with lysosomes. This impairment reduced the supply of nutrients such as glutathione and amino acids in addition to key cellular metabolites including Acetyl-CoA. "Taken together, the findings reveal a novel, evolutionarily conserved pathway that enhances the ability of multicellular organisms to digest lipids and survive starvation during periods of food deprivation," Emerling says.

Starving tumors

In a study published in the journal Cell in 2013, Emerling and Cantley found that a subset of breast cancers express high levels of PI5P4Kα and PI5P4Kβ. They also showed that these enzymes are essential for the growth of p53-deficient . Moreover, deficiency in Pip4k2a and Pip4k2b dramatically reduced tumor formation and increased tumor-free survival in mice lacking p53. But at the time, it was not clear exactly how PI5P4Ks promoted the growth of p53-deficient cancer cells.

The new study sheds light on this question, suggesting that these enzymes enhance the ability of to adapt to nutrient scarcity commonly found in the tumor microenvironment. Collectively, the studies suggest that PI5P4K inhibitors could effectively treat cancers with mutations in p53 by interfering with autophagy.

However, additional research is needed to dissect the distinct roles of the PI5P4Ks and their relationship with p53 in tumor metabolism. Emerling's lab is now focused on determining the role of the PI5P4K enzymes in p53-deficient cancers, especially the triple-negative breast cancer subgroup, which is associated with a poor prognosis due to the lack of effective targeted therapies.

"Given the high frequency of p53 mutations in human cancers, and how difficult it is to directly target p53 with drugs, our findings provide vital information for developing successful PI5P4K inhibitors for p53-mutant cancers," Emerling says. "These enzymes are extremely druggable, so it is exciting to think that targeting them with novel compounds could be an effective therapy for cancer and other autophagy-related conditions."

Explore further: Study reveals PGK1 enzyme as therapeutic target for deadliest brain cancer

More information: Molecular Cell (2018). DOI: 10.1016/j.molcel.2018.03.037

Related Stories

Study reveals PGK1 enzyme as therapeutic target for deadliest brain cancer

February 23, 2017
Discovery of a dual role played by the enzyme phosphoglycerate kinase 1 (PGK1) may indicate a new therapeutic target for glioblastoma, an often fatal form of brain cancer, according to researchers at The University of Texas ...

Link established between a molecular driver of melanoma and novel therapeutic agent

September 7, 2017
Results of a study by The Wistar Institute have described a correlation between a key melanoma signaling pathway and a novel class of drugs being tested in the clinic as adjuvant therapy for advanced melanoma, providing useful ...

Research reveals mechanism behind cell protein remodeling

September 3, 2014
The remodeling of a kitchen or bathroom changes the appearance of the room and improves its functionality. As investigators at Rutgers Cancer Institute of New Jersey and Rutgers and Princeton Universities have demonstrated, ...

Study suggests that autophagy inhibitors could improve efficacy of chemotherapies

October 24, 2016
Chemotherapies treat cancer by killing tumor cells, but certain types of chemotherapy can also drive an immune system response to target and destroy the remaining tumor cells.

Recommended for you

Function of neutrophils during tumor progression unraveled

October 15, 2018
Researchers at The Wistar Institute have characterized the function of neutrophils, a type of white blood cells, during early stages of tumor progression, showing that they migrate from the bone marrow to distant sites and ...

Delving where few others have gone, leukemia researchers open new path

October 15, 2018
A Wilmot Cancer Institute study uncovers how a single gene could be at fault in acute myeloid leukemia (AML), one of the deadliest cancers. The breakthrough gives researchers renewed hope that a gene-targeted therapy could ...

3-D mammography detected 34% more breast cancers in screening

October 15, 2018
In traditional mammography screening, all breast tissue is captured in a single image. Breast tomosynthesis, on the other hand, is three-dimensional and works according to the same principle as what is known as tomography. ...

More clues revealed in link between normal breast changes and invasive breast cancer

October 15, 2018
A research team, led by investigators from Georgetown Lombardi Comprehensive Cancer Center, details how a natural and dramatic process—changes in mammary glands to accommodate breastfeeding—uses a molecular process believed ...

Cancer stem cells use 'normal' genes in abnormal ways

October 12, 2018
CDK1 is a "normal" protein—its presence drives cells through the cycle of replication. And MHC Class I molecules are "normal" as well—they present bits of proteins on the surfaces of cells for examination by the immune ...

Obesity linked to increased risk of early-onset colorectal cancer

October 12, 2018
Women who are overweight or obese have up to twice the risk of developing colorectal cancer before age 50 as women who have what is considered a normal body mass index (BMI), according to new research led by Washington University ...

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.