Tuberous Sclerosis Complex (TSC) is an autosomal dominant disease that results from the hyperactivation of mammalian target of rapamycin (mTOR). The mTOR signaling pathway has emerged as a major node of cellular metabolism, cell proliferation, autophagy and immune response regulation. TSC null diseases, such as TSC1 null urothelial bladder cancer, are characterized by the functional loss of the tuberous sclerosis complexes 1/2 (TSC1 and TSC2), which are responsible for negatively regulating mTOR and maintaining cell homeostasis. The upregulation of mTOR stimulates tumor growth and proliferation and promotes the activation of its downstream targets, such as the 40S ribosomal S6 kinase 1 (S6K1) and S6. Rapamycin, an mTOR inhibitor, has clinically been used to treat TSC, however the inhibition of mTOR kinase activity stimulates autophagy and suppresses the negative feedback loop to Akt. The Akt pathway stimulates cell growth, and therefore rapamycin therapy is only partially effective and the disease is allowed to progress upon cessation of rapamycin treatment. Our research investigates whether a combinatorial approach of mTOR and autophagy inhibition with rapamycin and resveratrol, a naturally occurring polyphenol that has several known medically beneficial properties, may prove a more effective treatment for TSC. When TSC1 null and TSC2 null MEFs were treated with both rapamycin and resveratrol, autophagy was inhibited and apoptosis was initiated, as shown primarily by levels of protein markers for Akt, autophagy, and apoptosis. When tested in human bladder cancer cells, some of which contained the TSC1 mutation, the rapamycin/resveratrol combination produced a similar effect regarding increased apoptosis and autophagy inhibition. Our results indicate that the use of resveratrol in conjunction with rapamycin proves to be a more effective treatment for TSC1 null and TSC2 null diseases by inhibiting mTOR, preventing autophagy, and stimulating apoptosis.

Combined effects of resveratrol and rapamycin on TSC null diseases

251st National Meeting (2016)

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