It has been demonstrated that that cells lacking TSC2 have low levels of autophagy under basal and cellular stress conditions such as hypoxia and hypo-nutrition.
Using genetic and pharmacological approaches, however, it has been found out that the survival of Tsc2-deficient tumor cells is dependent on autophagy induction. In other words, Tsc2-deficient cells are highly dependent on autophagy for survival-an “Achilles’ heel.”
In the clinical settings, mTORC1 inhibitors, which activate autophagy, have partial efficacy in the treatment of certain manifestations of TSC, including angiomyolipomas, subependymal giant cell astrocytomas and LAM.
These facts seem to be quite puzzling and I wonder why the activation of autophagy with mTORC1 inhibitors such as sirolimus (rapamycin) induce the decreased TSC2-deficient cellular viability.
I am deeply appreciated if you would give me comments.
Thank you in advance!
Go
Hi!!. I think it is a very interesting question. Elizabeth Petri Henske has been working on this issue for a while. Rapamycin, apart of its role in autophagy activation, is an mTORC1 inhibitor and blocks cell proliferation. In fact, in our hands, using an in vitro model, autophagy activation in a chronic manner it is deleterious for cells. Rapamycin cannot be used for more than 24 hours. In the paper published in Autophagy by Henske´s lab indicates the following sentence: " The net result of these opposing influences (growth arrest and autophagy induction) may underlie the partial response observed in human TSC tumors upon treatment with mTORC1 inhibitors. Based on our data, we propose that autophagy inhibitors will have efficacy as single agents in TSC, and that the combination of autophagy inhibition with mTORC1 inhibition will have enhanced efficacy vs. either treatment alone". Article Autophagy An 'Achilles' heel of tumorigenesis in TSC and LAM
Furthermore, it seems that TSC2 -/- cells, which present and autophagy inhibition scenario, are more dependent on the pentose phosphate pathway to obtain energy.
It is very clear that TSC2 -/- cells present a defect in autophagy. However, can stimulate somehow this process to survive. So, if you stimulate autophagy with rapamycin and at the same time you block this survival mechanism appears a conflict in the cell that drives cells to apoptosis. In fact, TSC2-/- present an ER stress and are more vulnerable to cell death.
So, the treatment must be multifactorial, ni order to treat the disease from different approaches for the blockade of the different scape strategies that tumour cells use.
Thanks a lot for the question. Is is super-interesting
Carlos
Thank you for your kind reply.
TSC2-deficient cells seem to highly depend on autophagy for cellular survival although the autophagy activity in TSC2-deficient cells is relatively low as compared with TSC2-intact cells due to the enhanced level of mTORC1. It is quite paradoxical and puzzling, but it has been proposed that rapamycin, inducing autophagy, promotes the survival of LAM cells, while simultaneously arresting their growth. That is why combined inhibition of mTORC1 and an autophagy inhibitor such as chloroquine could have synergistic therapeutic effect.
Sincerely yours.
Go J. Yoshida MD, PhD.
It is highly likely that both mTOR signal and autophagy have the dual effect for cellular survival and proliferation. Furthermore, protein translation and autophagy seem to occur in a mutually exclusive manner.
When mTOR signal is suppressed, autophagy is activated, thus increasing the possibility of the cellular survival under the hypo-nutrient conditions. On the other hand, the protein synthesis is suppressed via p70S6K and 4E-BP1, thereby decreasing the possibility for cellular proliferation.
Surely the combination of mTOR inhibitor and autophagy inhibitor can be a promising therapeutic strategy, the influence can be cancelled each other.
I am appreciated if anybody would be kind enough to give your comment on this idea.
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