Sirt1 deficiency upregulates glutathione metabolism to prevent hepatocellular carcinoma initiation in mice.

Sirtuin-1 (SIRT1) is involved in various metabolic pathways, including fatty acid synthesis and gluconeogenesis in the liver. However, its role in initiation and progression of liver cancer remains unclear. Studying Sirt1 liver-specific knockout (LKO) mice in combination with diethylnitrosamine (DEN) treatment, we demonstrated that loss of Sirt1 rendered mice resistant to DEN-induced hepatocellular carcinoma (HCC) development. RNA-seq revealed that livers from LKO mice exhibited an enrichment in glutathione metabolism eight months after DEN challenge. Sirt1 deficiency elevated the expression of glutathione-s-transferase family genes by increasing the level of Nrf2, a key regulator of glutathione metabolism. Hence, LKO livers displayed a reductive environment with an increased ratio of GSH to GSSG and an elevated GSH level. Furthermore, using CRISPR knockout techniques, we confirmed that the impairment of HCC formation in LKO mice is mainly dependent on NRF2 signaling. Meanwhile, HCC induced by DEN could be blocked by the administration of N-acetyl cysteine (NAC) when administered one month after DEN challenge. However, NAC treatment starting five months after DEN injection was not able to prevent tumor development. In conclusion, our findings indicate that a reductive environment orchestrated by glutathione metabolism at an early stage can prevent the initiation of HCC.

Promise and pitfalls of immune checkpoint inhibitors in hepato-pancreato-biliary malignancies.

A growing understanding of the immune system and its anti-tumor functions has been imperative for the comprehension of malignant processes and beneficial in the pursuit of effective cancer treatments. To defend the body, immune cells must be able to differentiate between self and foreign cells using checkpoints, allowing the immune cells to attack foreign cells. Among the different types of immune target therapies recently developed, checkpoint inhibitors have come to the forefront in cancer treatment, encouraging their study in numerous different types of cancer, including hepato-pancreato-biliary malignancies (HPB). Traditionally, these malignancies have been treated with standard cytotoxic chemotherapy, but with little benefit in the metastatic setting. However, impressive results with checkpoint inhibitor therapy have been noted in a number of cancers as these agents enable immune cells to kill cancer cells more efficiently. Two classes of checkpoint inhibitors being extensively studied are inhibitors of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) ligand and programmed cell death protein 1 and its ligand (PD-1 and PD-L1). Checkpoint inhibitors have an advantage over other types of immunotherapies, such as cell-based therapies, in that they are commercially available and can be given to patients with a range of pathologies and regardless of HLA status. Herein, we will discuss the application of immune checkpoint inhibitors to HPB malignancies as well as the limitations of these medications in these cancers.