Resveratrol as a novel treatment for diseases with mTOR pathway hyperactivation

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is hyperactivated in a variety of cancers and tumor syndromes. Therefore, mTORC1 inhibitors are being actively investigated for treatment of neoplasms. The concern with the monotherapy use of mTORC1 inhibitors, such as rapamycin, is that they cause upregulation of autophagy, a cell survival mechanism, and suppress the negative feedback loop to the oncogene Akt. In turn, Akt promotes cell survival, causing the therapy to be partially effective, but relapse occurs upon cessation of treatment. In this review, we describe the current literature on resveratrol as well as our work, which uses rapamycin in combination with resveratrol. We found that this combination treatment efficiently blocked upregulation of autophagy and restored inhibition of Akt in different cancer and tumor models. Interestingly, the combination of rapamycin and resveratrol selectively promoted apoptosis of cells with mTOR pathway hyperactivation. Moreover, this combination prevented tumor growth and lung metastasis when tested in mouse models. Finally, mass spectrometry-based identification of cellular targets of resveratrol provided mechanistic insight into the mode of action of resveratrol. The addition of resveratrol to rapamycin treatment may be a promising option for selective and targeted therapy for diseases with mTORC1 hyperactivation.

Resveratrol fuels HER2 and ERα-positive breast cancer behaving as proteasome inhibitor

“…Consistently, we have reported the resveratrol-induced over-expression of Δ16HER2 eventually results in the activation of mTORC1/p70S6K/p4EBP1 axis. This observation recapitulates a relevant molecular pathway implicated in endocrine resistance development [44] and may explain why the combination of resveratrol and mTORC1 inhibitors have stood out as more effective anti-tumor therapy than single-agent approaches [45, 46]. …”

GADD34 Keeps the mTOR Pathway Inactivated in Endoplasmic Reticulum Stress Related Autophagy

“…As it was mentioned before resveratrol is able to down-regulate mTOR and up-regulate AMPK, therefore induces autophagy [22]. To confirm its positive role during ER stress cells were pre-treated with resveratrol (10 μM) for 24 hours then ER stress was induced by TG (10 μM– 2 hours).…”

“…Resveratrol addition seems to be a promising treatment for various diseases with mTOR hyperactivation (such as cancer, lymphangioleiomyomatosis). Resveratrol is able to down-regulate mTORC1 both directly and indirectly via AMPK activation, therefore it promotes autophagy [21, 22]. …”

p53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing

“…The observation that Met and Rsv have protective roles against premature decidual senescence-associated PTB is an exciting development since both are now known to have anti-aging properties and reportedly extend lifespan (17,44). Met can inhibit mTORC1 activity via AMPK-dependent or -independent pathways (7), whereas Rsv inhibits the hyperactivated mTORC1 pathway (45). Although mTORC1 signaling has taken center stage in cellular senescence, our in vivo and in vitro results suggest that a tightly regulated reciprocal integration of AMPK and mTORC1 signaling together plays a significant role in the decidual senescence in both mice and humans.…”