There’s a new report in Molecular Cell (29, 541-551) from Gokhan Hotamisligil’s group suggesting that cellular stress might actually be helpful in certain contexts.
The Hotamisligil lab has published numerous reports on the importance of endoplasmic reticulum (ER) stress in metabolic dysfunction. Their previous data have suggested that insulin resistance (pre-diabetes, if you will) leads to a greater demand for insulin from the pancreatic beta cells. But this increased demand means more protein production, which can stress the ER and result in apoptosis. If this occurs in the islets overt diabetes can result.
In addition to his basic science experience, Gokhan also has a clinical background and he mentioned to me once that he used to see tuberous sclerosis complex (TSC) patients and was struck by the numerous benign tumors that form throughout their bodies. Now his interests are coming full circle as his group is reporting on ER stress in TSC and a potential therapy angle that could result from this insight.
The normal versions of the disease genes of TSC, TSC1 and TSC2, encode for proteins that form a complex that inhibits mTOR, the mammalian target of rapamycin. mTOR is a critical protein that integrates the nutritional state of the cell and cell growth by activating nuclear factors that control protein translation in response to increased amino acid levels. So TSC deficiency results in hyperactivation of mTOR, which leads to increased cell growth and is probably an explanation for the high number of benign tumors in these patients. While rapamycin, an inhibitor of mTOR, is a possible therapeutic treatment for TSC sufferers, it also has many nasty side-effects, especially over the long-term, so its potential in this regard is rather limited.
Given the increased protein production that results when mTOR is hyperactivated, it is possible that ER stress could occur in TSC-deficient cells. In this new report, Umut Ozcan et al. now show that lack of TSC does result in ER stress, including in the tumors that form in the Tsc2 KO mouse, as well as in a resected human TSC-derived tumor. They also show that this ER stress results in insulin resistance, tying in these results with the lab’s previous studies.
Clearly the level of ER stress caused by the defect in TSC, however, is not sufficient to cause apoptosis given the high number of benign tumors that form in this disease. But the team reasoned that if TSC1- or TSC2-deficient cells were treated with thapsigargin, a chemical inducer of ER stress, then perhaps they could tip the balance towards cell death. They were able to show this and, importantly, at the dosage of thapsigargin used normal cells were not killed. This result indicates the absence of TSC makes cells more vulnerable to ER-stress-induced apoptosis, which the group then used to their advantage in vivo. They injected Tsc2+/- mice, which develop kidney adenomas after 1 year, with thapsigargin once a day for a week and that resulted in apoptosis in the tumor cells but not in nearby healthy tissue. It wasn’t reported, however, if this treatment was sufficient to shrink the tumor or return normal kidney function.
These findings are summarized in this schematic from the paper:
These results suggest a possible way to treat TSC. Unfortunately thapsigargin is too toxic and too blunt a tool to be used in the clinic. For example, pancreatic beta cells, even healthy ones, are quite vulnerable to ER stress-induced apoptosis. But nonetheless this study does point in a new direction for the development of a future therapeutic option in treating cancers that involve hyperactivation of mTOR.