UCLA research shows that biological sex may significantly impact how metabolism affects lung tumor growth, highlighting the importance of considering biological sex in metabolic cancer interventions and personalized treatment approaches.
- A diet with 2% calcium alpha-ketoglutarate (Ca-αKG) reduced lung tumor growth in female mice but increased tumor size in male mice.
- The supplement works by modifying gene expression through epigenetic remodeling, not by changing tumor number.
- Higher TBX5 levels in female patients were associated with decreased tumor cell proliferation and improved five-year survival rates.
Recent research out of the UCLA Health Jonsson Comprehensive Cancer Center reports the important role of biological sex and tumor genetics in metabolic approaches to cancer treatment and prevention. The paper, “Dietary α-Ketoglutarate Modulates Lung Adenocarcinoma Growth and Epigenetic Remodeling in a Sex-Dependent Fashion,” was published in the journal, Cell Reports.
In particular, the investigators identified a dietary form of calcium alpha-ketoglutarate (Ca-aKG) that reduced lung tumor growth in female mice but increased tumor size and tumor cell production in male mice. This suggests Ca-aKG impacts lung cancer progression and outcomes by chemically modifying gene expression, the researchers said.
“These findings offer a glimpse into the complicated relationship among metabolism, cancer and biological sex. The fact that we observed opposite reactions in male and female mice underscores the importance of understanding how sex and tumor genetics shape the response to these types of interventions,” said senior author Claudio Scafoglio, MD, PhD, in a university news release. Dr. Scafoglio is an associate professor of pulmonary and critical care medicine at UCLA.
The researchers sought to learn more about how aKG — a naturally occurring molecule that helps generate cellular energy and is involved in epigenetic regulation — impacts lung tumor growth. They worked with genetically engineered mice that developed lung adenocarcinoma via a KRAS mutation.
Mice were assigned either a diet containing 2% Ca-aKG or a control diet. At the end of the 16-week period, female mice in the Ca-aKG cohort had significantly smaller tumors as well as reduced tumor cell proliferation than the female mice in the control group. The opposite was true in male mice.
A figure showing lung sections from male and female mice in the two groups. The tumors are highlighted by the red areas.UCLA | Scafoglio Laboratory
When analyzing its effect on tumors’ molecular makeup, Ca-aKG decreased two repressive histone modifications (H3K27me3 and H3K9me3) in female mouse tumors, the researchers reported, thereby limiting the activity of certain genes. In male mice, however, they said the supplement increased H3K27me3, producing the opposite epigenetic effect.
The researchers further detailed how Ca-aKG affected a gene program that is seldom linked to epithelial tumors and is more frequently associated with myogenesis, or muscle development. In female mice, the supplement stimulated these genes, while it suppressed the same genes in male mice.
Based on the results, the researchers said TBX5 could be a possible regulator of Ca-aKG response. Data from The Cancer Genome Atlas indicated higher TBX5 levels in female patients, which were associated with decreased tumor cell proliferation and improved five-year overall survival rates. However, further research is required to confirm any connection between TBX5 and Ca-aKG, the researchers noted, since these patients were not treated with Ca-aKG. Additional studies are also needed to validate the contrasting responses by sex and genetic background.
“These findings highlight how a metabolic intervention can have broad effects on the cancer genome, not only by changing the energetic state of cancer cells, but also by directly affecting gene regulation. Cellular metabolism is tightly linked to epigenetic state via a complex network of interdependent pathways,” Dr. Scafoglio said. “This study is an early step toward the full characterization of metabolic and epigenetic modifications induced by nutritional interventions.”
