Autophagy is a process vital for cell survival whereby cells digest and recycle damaged components.
Hexokinase2 (HK2), the enzyme in question, is vital for glucose metabolism in cancer cells. By destroying this metabolic enzyme, methods of treatment may stop cancer cells from making use of absorbed glucose and stored nutrients, leading them to die.
The study was conducted by researchers at Harvard Medical School in Boston, MA, and it is published in The Journal of Cell Biology.
Cancer cells make use of a process known as autophagy in order to survive inside tumors. With this process, any damaged components of the cell are digested and recycled. While the process is key to the survival of cancer cells, however, blocking it is not enough to kill cells off.
As a result, researchers have been searching for ways in which cancer cells can be made more vulnerable to treatment that prevents autophagy from occurring.
For their study, the researchers at Harvard Medical School tested more than 8,200 compounds on an ovarian cancer cell line known to be resistant to spautin-1 – an inhibitor of autophagy – or an upgraded version of this inhibitor.
They discovered that quizartinib, a drug that is currently being trialled as a form of treatment for acute myeloid leukemia (AML), was the most effective compound for making the cancer cells more susceptible to the effects of the autophagy inhibitors.
Quizartinib works by inhibiting an enzyme called FLT3 that plays an important role in ensuring that stem cells in the blood develop correctly. While the drug is recognized as having value in treating AML, its use outside of this has yet to be fully explored.
Quizartinib and upgraded spautin-1 initiated chaperone-mediated autophagy
When cancer cells were treated with quizartinib, an important metabolic pathway known as glycolysis was successfully inhibited. However, this led to the activation to a form of autophagy known as macroautophagy, whereby the cell digests a large proportion of its contents.
The researchers also treated cancer cells with quizartinib and the upgraded version of spautin-1 and had much greater success. Tumor cells from a variety of cell lines were killed and noncancerous cells were unaffected.
They found that cancer cells treated with both compounds were unable to activate macroautophagy. Instead, a more selective form of autophagy known as chaperone-mediated autophagy was initiated.
HK2 was one of the individual targets selectively eliminated by this process, and consequently its elimination may have led to the death of these cancer cells.
Autophagy plays an important role in the prevalence of other conditions apart from cancer. For example, Medical News Today reported on a study last year that found autophagy is reduced in the brains of people with schizophrenia.
The researchers found that patients with schizophrenia had reduced levels of a protein called beclin-1 in the hippocampus – a protein that plays an important role in autophagy.
Written by James McIntosh