Suppression of stress-induced enzyme as therapeutic target for liver cancer

EXPRESSION of an enzyme as a stress-response upregulates significant proliferation pathways in the progression of liver cancer, according to a new study.

The enzyme, Nqo1, which is induced in response to stress, has also been shown to be utilised by liver cancer in the upregulation of the PI3K/Akt and MAPK/ERK pathways. These pathways are key in the metabolic processes implicated in cancer that allow the cancer to use glucose as fuel and for rapid replication of cancer cells. By blocking Nqo1, “the proliferation of liver cancer cells is dramatically suppressed,” noted Dr Satya Ande, Molecular Biologist, MCG Department of Biochemistry and Molecular Biology, Georgia Cancer Center, Augusta, Georgia, USA.

Authors of the study reported that the tumour suppressor PTEN is a key target of Nqo1, which works against PI3K/Akt and MAPK/ERK pathways. Increased levels of PTEN opposes the ‘Warburg effect’, the rewiring of cancer cell metabolism to optimise use of glucose as fuel, hence having the opposite effect of Nqo1. Nqo1 targets not one, but two significant downstream pathways; consequently, this enzyme is considered to be a prime therapeutic target in the treatment of certain cancers that it is shown to be implicated in, such as cancers of the breast, ovaries, pancreas, and thyroid.

The researchers were able to identify genes upregulated in liver cancer in mice by initial comparison of cancerous and normal livers. At this stage, Nqo1 was confirmed as being highly upregulated, “a logical next question was what the Nqo1 is doing in liver cancer,” said Dr Manali Dimri, postdoctoral fellow, MCG Department of Biochemistry and Molecular Biology, Georgia Cancer Center, Augusta, Georgia, USA. Drugs were identified which were able to suppress the enzymatic activity and free radical scavenging of Nqo1 but had no effect on liver cancer cells ability to replicate. The authors plan to execute a large screening of existing drugs to decipher those able to suppress Nqo1.

The authors of this study used liver cancer models to investigate Nqo1 behaviour in liver cancer and plan to further explore the enzymatic activity in other cancers.