A recent study entitled “Diet-Induced Unresolved ER Stress Hinders KRAS-Driven Lung Tumorigenesis” revealed a surprising beneficial role of high-calorie-diet intake in limiting the proliferation of lung-tumors, driven by KRAS mutation, when ingested before tumor onset. The study was published in the journal Cell Metabolism.
In this study, a team of scientists from the Department of Cell Physiology and Metabolism at the Faculty of Medicine of the University of Geneva (UNIGE), Switzerland with colleagues at the University of Texas Southwestern Medical Center and Ancona University, sought to seek the effects of a high-calorie-diet (HCD) intake if administered to mice before the onset of lung-tumors. The authors used a mouse model with mutations in a well-established oncogene, KRAS, which leads to tumor formation in lungs, pancreas and colon, and is susceptible to dietary intake.
The authors found that when KRAS mutant mice are fed with a HCD before tumor onset, they exhibit an impaired growth of KRAS-driven lung tumors. However, if the HCD is administered after lung-tumor onset, it promotes tumorigenesis. Therefore, HCD administration has a dual effect on KRAS induced lung tumorigenesis, dependent on when during tumor progression the diet is introduced.
The authors performed further studies to understand the underlying molecular mechanisms behind the anti-tumorigenic effect of HCD. They observed that HCD before tumor-onset resulted in an impaired Unfolded Protein Response (by the Endoplasmic Reticulum, ER), leading to an unresolved ER stress response in tumor cells, that fail to properly respond to this stress, resulting in an impairment of their proliferative capacities.
The team performed further experiments and identified a specific chaperone protein –FKBP10 – whose expression is restricted to cancer-tissues, was significantly reduced by HCD. Since ER stress is resolved through the activation of ER chaperones, the dampening of FKBP10 was a potential candidate for the observed effect induced by HCD. Accordingly, the authors observed that reducing FKBP10 expression impaired tumor growth in vivo, which was achieved by reducing cellular proliferation.
These results open the possibility of FKBP10 as a potential selective new target for the development of new therapeutic for lung-cancers carrying the potential of not harming lung health-tissue.
Roberto Coppari, study leading author commented in a news release, “FKBP10 was not previously thought to be important for cancerous cells. In this study we show that knock-down of FKBP10 leads to reduced cancer growth. Human lung cancer cells express FKBP10 while the nearby healthy lung tissue does not; this is very interesting and appealing to eventually translate these findings to the clinical arena. Hence, if we manage to identify the right inhibitor, we may open the door to new therapeutic strategies that will be able to hinder cancer cells proliferation without damaging the healthy cells. The inhibition of this protein is predicted to have minimal side effects as it is not expressed in healthy tissues, at least in adulthood.”