Scientists at the Cincinnati Children’s Cancer and Blood Diseases Institute (CCCBDI) have demonstrated that AMP-activated protein kinase (AMPK) – an enzyme believed to play an important role in the suppression of cancer – may actually be a major driver of aggressive brain cancers such as glioblastoma multiforme (GBM).
GBM is particularly aggressive and occurs in the brain or spinal cord, It results in the formation of astrocyte cells that support nerve cells. This form of cancer is difficult to treat as the cells are particularly resistant to standard treatments. Many drugs cannot pass through the blood brain barrier to act on the tumor and the brain is particularly susceptible to damage from conventional therapy. For many patients, treatment is not possible. When it is, it will only slow the progression of the disease and alleviate some of the symptoms. With treatment, life expectancy is only around 14 months. However, the research conducted by CCCBDI scientists hints at a potential new treatment for GBM and other forms of cancer.
AMPK serves as a bioenergetics sensor that helps to regulate cell metabolism and stress. While the enzyme has been shown to help suppress certain cancers, recent research has suggested that AMPK can actually have an oncogenic role in astrocytic tumors of the brain.
While searching the Cancer Genome Atlas looking for metabolic kinases that are differentially expressed in cancers, the researchers discovered expression of AMPK catalytic subunits α1, β1, and γ1 was upregulated in GBM and higher expression of activated AMPK (pAMPK) corresponded with lower survival rates with patients with lower-grade gliomas (LGG).
Further research suggested high AMPK activity in GBM tumors and primary GBM stem cell lines isolated from fresh tumors was due to oncogenesis-associated stress (OAS), which effectively activated AMPK.
The researchers demonstrated that blocking the action of AMPK reduced the growth of GBM stem cells when transplanted in mice, which increased survival rates. While studies need to be conducted to demonstrate that the inhibition of AMPK is safe in humans, the CCCBDI study showed that the treatment appears to be safe in mice.
“AMPK is considered to play a suppressive role in cancer because it inhibits cancer-promoting enzymes like mammalian target of rapamycin (mTOR) and acetyl Co-A carboxylase (ACC),” said Biplab Dasgupta, Ph.D., senior researcher for the study at Division of Oncology at CCCBDI.
Dasgupta explained that his team’s research showed that “inhibiting AMPK by genetic means shrinks brain tumors and prolongs survival in mice.” The researchers also showed that deleting AMPK from the whole body of adult mice was shown to be safe.
The team developed a variety of methods to deplete AMPK and adult mice with systemic AMPK knockdown lived a normal lifespan with no observed metabolic effects.
The research suggests AMPK inhibition could be a viable treatment for GBM in humans, and while it is likely to be many years before such a treatment could be developed, it is hoped that the research will encourage drug companies to start screening for potential AMPK inhibitors.
The research is detailed in the paper – AMP Kinase Promotes Glioblastoma Bioenergetics and Tumour Growth – which was recently published in the journal Nature Cell Biology: DOI: 10.1038/s41556-018-0126-z