# Deficiency of PTEN Confers Hypersensitivity to Fatty Acid-Mediated ER Stress in Transformed Hepatocytes

## TL;DR

PTEN-deficient liver cancer cells are highly sensitive to fatty acids, leading to cell stress and death, suggesting dietary or drug strategies could target these tumors.

## Contribution

PTEN-deficient hepatocytes show unique vulnerability to fatty acid-induced ER stress and apoptosis, offering new therapeutic opportunities.

## Key findings

- PTEN-deficient HepG2 cells undergo ER stress and apoptosis when exposed to fatty acids, unlike control cells.
- PTEN KO cells show increased triglycerides and impaired lipid droplet formation, along with reduced β-oxidation.
- PTEN-deficient tumors grow faster on normal diets but slower on high-fat diets, indicating metabolic vulnerability.

## Abstract

Deletion of the tumor suppressor gene phosphatase and tensin homolog (PTEN) in hepatocellular carcinoma (HCC) is associated with a poor response to therapy and reduced survival. In mice, the deletion of PTEN in hepatocytes generates steatosis; however, on the background of steatosis not all emerging HCC cells lack PTEN, suggesting that steatosis confers a metabolic liability to proliferating PTEN-deficient hepatocytes. Here, we show that PTEN-deficient HepG2 cells develop terminal stress in the endoplasmic reticulum (ER) and profound apoptosis when exposed to a mixture of oleic and palmitic acids, while control cells do not. Lipidomic analyses before and after the treatment indicate a higher increase in triglycerides in PTEN KO cells, as well as profound differences in phospholipid concentrations. Although the triglyceride content increases, the coalescence into lipid droplets was impaired in the KO cells, together with a reduction in β-oxidation. Xenograft studies showed that PTEN KO HCC tumors progressed faster than did the control tumors when mice were fed with normal chow and slower under a high-fat diet. We suggest that while the health risks of a fatty acid-rich diet to liver function and the increased propensity to develop HCC are prominent, once a PTEN-deficient HCC has been established, it exposes vulnerability to lipid overload that can be exploited through diet and pharmacological interventions.