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.
Yassin et al. (Thu,) studied this question.