Year-end Sale % OFF 
Abstract
Mutations in tuberous sclerosis (TSC) genes cause the genetic disorder TSC, as well as other neoplasms, including lymphangioleiomyomatosis (LAM) and angiomyolipomas (AMLs). AMLs are benign renal tumors occur both in sporadic LAM and in TSC. As they carry the same mutations, AML cell lines serve as a model for TSC and LAM. Rheb/mammalian target of rapamycin complex 1 (mTORC1) pathway is chronically activated in TSC-deficient cells, and this activation can be diminished using the appropriate inhibitors. Rapamycin (sirolimus) is a known specific inhibitor of mTORC1, whereas S-trans,trans-farnesylthiosalicylic acid (FTS; salirasib) has been shown to inhibit Rheb. To examine the effect of the Rheb/mTOR inhibition pathway, we used human TSC2-deficient AML cells, derived from a LAM patient. FTS indeed inhibited Rheb in these cells and attenuated their proliferation. After comparative treatments with FTS or rapamycin or by re-expression of TSC2, we carried out a gene array analysis. This yielded a substantial number of commonly altered genes, many of which we identified as downstream targets of the interferon (IFN) regulatory factor 7 (IRF7) transcription factor, a central activator of the IFN type 1 immune response. Furthermore, nuclear localization of IRF7 was impaired by each of the three treatments. Interestingly, the phenomena seen on FTS or rapamycin treatment were selective for TSC2-deficient cells. Moreover, knockdown of IRF7 by siRNA mimicked the decrease in number of the abovementioned genes and also inhibited AML cell proliferation. Altogether, these findings support FTS as a potential treatment for TSC and its related pathologies and IRF7 as a novel target for treatment.
Highlights
About 80% of Tuberous sclerosis (TSC) patients and 40% of patients with sporadic LAM (S-LAM) will develop renal angiomyolipomas (AMLs), benign kidney tumors containing fatty tissue, smooth muscle cells and dysplastic blood vessels.[6,7,8] AML cells closely resemble
We used the AML cell line, 621, which is derived from a LAM patient and is deficient in TSC2.7 Having already shown that FTS inhibits the growth of TSC2deficient rat ELT3 cells and inhibits Rheb but not Ras in those cells,[14] we wanted to substantiate those observations in a human model
We showed that FTS can inhibit the growth of a rat cell line and of a human TSC2-deficient AML cell line, which was derived from a LAM patient and can serve as a model for LAM27 (Figure 1a)
Summary
About 80% of TSC patients and 40% of patients with S-LAM will develop renal angiomyolipomas (AMLs), benign kidney tumors containing fatty tissue, smooth muscle cells and dysplastic blood vessels.[6,7,8] AML cells closely resemble. LAM cells, as both carry inactivating mutations in either the TSC1 or the TSC2 gene.[7,9,10] Previous studies raised the hypothesis that renal AML cells can generate pulmonary LAM by metastasizing into the lung.[7,11]. Rapamycin (sirolimus), a known inhibitor of mTORC1, has already been tested in LAM patients in the Multicenter. International LAM Efficacy of Sirolimus (MILES) trial and has shown promising results that include improvement in lung function and alleviation of symptoms.[17]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
