Nature Medicine | Spoonful of Medicine

Stress as a therapy?

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:

TSC-Mol Cell Summary schematic.bmp

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.

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    Sergio Stagnaro MD said:

    This really interesting news, referring to an excellent article, concludes: “…this study does point in a new direction for the development of a future therapeutic option in treating cancers that involve hyperactivation of mTOR”. First of all, the article from Gokhan Hotamisligil’s group underscores the central role played by TSC-deficiency in both Insulin-Resistance and apoptosis, as well as increased cell growth. I am delighted with such as paper. In fact, as I wrote also in Sponful of Medicine, I discovered and described a long time ago, from clinical viewpoint, numerous biophysical-semeiotic constitutions, among them the diabetic and oncological ones (Oncological Terrain). Notoriously, diabetes and cancer are associated often – certainly not due to casualty, i.e., by chance – in the same individuals. In a few words, the referred genetic, molecular-biological,oustanding results by Gokhan Hotamisligil’s group, agree with my old clinical data, indicating the existance of a bedside demarcation line (constitutions) in all most common and severe disorders, including diabetes and cancer. My 52-year-long clinical experience allows me to state that oncogenesis is possible exclusively in individuals Oncological Terrain-positive, involved by Inherited Oncological Real Risk .In my opinion, because the congenital functional mitochondrial cytopathology, which is the “conditio sine qua non” of the most common and dangerous human disorders, including malignancy, both solid and liquid, is overlooked, all current oncological primary preventions are fundamentally biased, and thus scarsely efficacious. I mean that authors do not consider the existence or assess the seriousness as well as the location of Congenital Acidosic Enzyme-Metabolic Histangiopathy, Oncological Terrain and thus Oncological Inherited Real Risk is based on, since such as mitochondrial cytopathology is overlooked (1-8). In fact, both environmental risk factors and every drug, as oestrogens, suggested as cancer risk factors, “could” influence some human biological functions and/or bring about different disorders, like cancers, exclusively in relation to both the presence and intensity of CAEMH-dependent Oncological Terrain and Oncological Inherited Real Risk in well-defined site of a (or more) biological system. I suggested this overlooked functional mitochondrial cytopathology, I have termed Congenital Acidosic Enzyme-Metabolic Histangiopathy, biophysical-semeiotic constitutions are based on, as the genetic factor of common human disorders, and particularly of malignancy (1-8). (“Oncological Terrain”,in: http://www.semeioticabiofisica.it), as far as the onset of a lot of disorders is concerned. At this point, I would analogously emphasise the well-known pathological powerful influence of smoking on tissue oxygen supply to all biological systems (3, 4). This effect varies notoriously in prevalence and intensity among individuals in relation to the above-mentioned congenital mitochondrial cytopathology, (2). This both “silent” and dangerous action is easy to evaluate at the bed-side with the aid of a stethoscope. Based on my long clinical experience, I suggest first investigating (i.e., before whatever research) the presence and intensity of CAEMH in the “tested” population, and soon thereafter assessing prevalence and intensity of the “Oncological Terrain” as well as Inherited Oncological Real Risk, which always develop on the basis of the above-mentioned congenital cytopathology, characterized by newborn-pathological, type I, subtype a), oncological, Endoarterial Blocking Devices, causing the typical microvascular remodelling (1-8). In fact, without this alteration of psycho-neuro-endocrine-immunological system, oncogenesis is not possible. The importance of the above-mentioned inherited real risk factor should not be overlooked from now on, particularly when we assess a “possible” risk factor for disorders biophysical-semeiotic constitution-dependent (9, 10).

    1) Stagnaro S., Stagnaro-Neri M.Istangiopatia Congenita Acidosica Enzimo Metabolica. Gazz. Med. It.- Arch. Sci. Med. 144, 423, 1985.

    2) Stagnaro S., Stagnaro-Neri M. Una patologia mitocondriale ignorata: la Istangiopatia Congenita Acidosica Enzimo-Metabolica. Gazz. Med. It. – Arch. Sci. Med. 149, 67 1990.

    3)Stagnaro-Neri M., Stagnaro S. Deterministic Chaos, Preconditioning and Myocardial Oxygenation evaluated clinically with the aid of Biophysical Semeiotics in the Diagnosis of ischaemic Heart Disease even silent. Acta Med. Medit. 13, 109 1997.

    4) Stagnaro-Neri M., Stagnaro S., Cancro della mammella: prevenzione primaria e diagnosi precoce con la percussione ascoltata. Gazz. Med. It. � Arch. Sc. Med. 152, 447 1993

    5) Stagnaro-Neri M., Stagnaro S. Introduzione alla Semeiotica Biofisica. Il Terreno Oncologico. Ed. Travel Factory, Roma, 2004. http://www.travelfactory.it/semeiotica_biofisica.htm

    6) Stagnaro S., Stagnaro-Neri M., Oncological Terrain, conditio sine qua non of Oncogenesis, 2004: http://www.gutjnl.com/cgi/eletters?lookup=by_date&days=60

    7) Stagnaro Sergio. “Genes, Oncological Terrain, and Breast Cancer” World Journal of Surgical Oncology., 2005, http://www.wjso.com/content/3/1/45/comments#205475

    8) Stagnaro S. Reale Rischio Semeiotico-Biofisico. Ruolo diagnostico e patogenetico dei Dispositivi Endoarteriolari di Blocco neoformati patologici tipo I, sottotipo a) oncologici e b). Ed Travel Factory, Roma, http://www.travelfactory.it, in press

    9) Stagnaro S. Newborn-pathological Endoarteriolar Blocking Devices in Diabetic and Dislipidaemic Constitution and Diabetes Primary Prevention. The Lancet. March 06 2007. http://www.thelancet.com/journals/lancet/article/PIIS0140673607603316/comments?totalcomments=1

    10) Sergio Stagnaro. Mitochondrial Genome of the Mastodon highlights Human Constitutions. PLOS Biology, (01 August 2007) http://biology.plosjournals.org/perlserv/?request=read-response&doi=10.1371/journal.pbio.0050207#r1725

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    yvonne said:

    Hi,

    Great site!!!!! Good health is very important with the high cost of medical coverage. We need to have a healthier lifestyle by taking care of our health eating and exercising and also avoiding stress. I am a cancer survivor and I know. Our health is our greatest asset. Keep up the Good Work!!!!!