Gastroenterology

The researches find that the enzyme induced by stress to help reduce production of damaging free radicals is also used by liver cancer to regulate two major cell proliferation pathways that enable the cancer to thrive, scientists report. They’ve also found that when they block the enzyme Nqo1, it dramatically reduces the proliferation of liver cancer cells; a hallmark of cancer’s ability to survive and thrive; they report in the journal HEPATOLOGY. Nqo1 is highly express in both their mouse model of liver cancer and in human liver cancer where scientists at the Georgia Cancer Center and Medical College of Georgia at Augusta University have found it acts upstream to activate the PI3K/Akt and MAPK/ERK pathways.

Liver cancer to regulate

Both pathways are key to enabling the metabolic reprogramming that enables cancer cells’ super-efficient use of glucose as fuel and ultimately their rapid replication. Knocking out Nqo1 blocks the metabolic adaptation needed to enable liver cancer cell proliferation, says Dr. Satya Ande; molecular biologist in the MCG Department of Biochemistry and Molecular Biology and Georgia Cancer Center. “The proliferation of liver cancer cells is dramatically suppress;” he says.

Proliferation and cell survival are likely the most important functions of these key pathways; which normally function at a low; basal level; says MCG postdoctoral fellow Dr. Manali Dimri. Somehow these pathways are also interacting with each other via different target genes. And; eventually, they are working together for cell proliferation; migration and metabolism.” Dr. Manali Dimri, MCG postdoctoral fellow Natural tumor suppressors are regularly inactivate in cancer, and Ande and Dimri also find that in  the tumor suppressor PTEN is another primary target of Nqo1, but in this case; it’s turning PTEN down.

Migration and metabolism

One way PTEN works is directly oppose to the work of Nqo1 in liver cancer because PTEN works against the PI3K/Akt and MAPK/ERK pathways. PTEN elevation can directly combat the so-called Warburg effect, which is cancer cells’ heightened use of glucose for fuel. The fact that Nqo1 targets two rather than a single  important downstream pathways, increases its value as a likely treatment target; Dimri says. The reality that Nqo1 is highly expressed in other cancers as well like breast, pancreas, ovarian and thyroid cancers; suggests it has a role in and may be a good therapeutic target for those as well, Ande says.

They started their work to find a better way to kill  by comparing normal mouse livers to cancerous ones to identify the likely long list of genes upregulated in liver cancer compared with a healthy liver. That’s when they find Nqo1 is highly upregulat; and a logical next question was what the Nqo1 is doing in liver cancer, Dimri says. High expression of Nqo1 has generally been correlate with increased tumor size, a more advance stage of cancer and ultimately decrease patient survival. But how it aids cancer cell proliferation has mostly remained a mystery.