Liver cancer cells that survive methionine restriction develop phenotypes of persistent cancer cells

Authors

• Q Xu
• XL Li

Abstract

Liver cancer, the third leading cause of global cancer death, is notoriously resistant to conventional chemotherapy or radiotherapy. We previously showed that liver cancer cells expressing high levels of hepatocyte nuclear factor 4a (HNF4a), the master regulator of liver cell identity, are sensitive to methionine restriction (MR), a dietary intervention that has been shown to inhibit tumor growth and improve cancer therapy. Here we report that some HNF4a positive liver cancer cells can manage to evade MR-induced cell death and develop typical phenotypes of persistent cancer cells, the major contributors to tumor relapse and metastasis.

MR-resistant liver cancer cells displayed slow proliferation, reduced protein synthesis, mesenchymal-like morphology, increased collagen deposition and cell migration as well as reduced intracellular gaseous transmitter hydrogen sulfide. At the molecular level, MR-resistant cells showed increased expression of markers for epithelial-to mesenchymal transition (EMT), a process associated with tumor metastasis and drug resistance. The expression of key enzymes involved in metabolism of sulfur amino acids (SAA) was significantly changed. Importantly, the expression levels of HNF4a protein, but not the mRNA, were drastically reduced in MR-resistant cells. Since we previously observed that knockdown of HNF4 is sufficient to increase resistance to MR, downregulation of HNF4 protein and the resulting SAA metabolic rewiring could promote the survival of liver cancer cells under MR. Understanding pathways responsible for the establishment of liver cancer persisters tolerant to MR will be valuable for developing new therapies to prevent recurrence and progression of liver cancer.

Scientific Focus Area: Cancer Biology

This page was last updated on Monday, September 25, 2023