Curcumin and piperine inhibit mTORC1 signaling in intestinal epithelial cells

Abstract

Persistent mTORC1 activation is not only linked to metabolic disorders but also cancer and inflammation by inducing transcription and translation of pro‐inflammatory cytokines. Gastrointestinal cancers are frequently associated with chronic inflammation and excessive secretion of IL‐6 family cytokines, which promote tumorigenesis through persistent activation of PI3K/mTORC1 pathway. Curcumin is the major natural phenol in turmeric, Curcuma longa. Curcumin inhibits a number of different molecules that play a role in inflammation such as TNFα, cyclooxygenase‐2, inducible nitric oxide synthase. Curcumin like many other dietary phenolic compounds has poor bioavailability in part due to extensive metabolism in the intestinal mucosa. Piperine, one of the major components of black pepper, has been shown to increase the bioavailability of dietary phenolics including curcumin. The long‐term objective of the study is to determine whether curcumin and piperine have individual and combined effects in the prevention of gut inflammation via inhibition of mTORC1 in Caco‐2 and HT‐29 cells. Results show that curcumin inhibited mTORC1 activity (phosphorylation state of its downstream targets, ribosomal protein S6 kinase β‐1 and ribosomal protein S6) in a dose dependent manner (ribosomal protein S6 phosphorylation: −52% at 2.5 μM, −84% at 20 μM, P<0.05). Piperine inhibited mTORC1 activity in its own right (ribosomal protein S6 kinase β‐1 phosphorylation: −84% at 2.5 μM, −91% at 20 μM, P<0.05). The combination of curcumin + piperine further inhibited the mTORC1 signaling. mTORC1 activity was markedly elevated (+2600%) in undifferentiated vs. differentiated Caco‐2 cells. Since epithelium dedifferentiation precedes the release of pro‐inflammatory cytokines and the neoplastic process, we are investigating the link between mTORC1 and the pro‐inflammatory cascade in these cells, and how curcumin +/− piperine mitigate these events. We conclude that widely available dietary phenolics, curcumin and piperine, have the potential to regulate the mTOR pathway in the intestine. While curcumin and piperine inhibit mTORC1 signaling independently of each other by mechanisms yet to be characterized, piperine may also indirectly potentiate curcumin activity through enhancement of its bioavailability.Support or Funding InformationSupported by USDA‐NIFA.