Targeting the PI3K/Akt/mTOR signaling pathway by pterostilbene attenuates mantle cell lymphoma progression

Abstract

Mantle cell lymphoma (MCL) is an aggressive and mostly incurable B-cell malignancy with frequent relapses after an initial response to standard chemotherapy. Therefore, novel therapies are urgently required to improve MCL clinical outcomes. In this study, MCL cell lines were treated with pterostilbene (PTE), a non-toxic natural phenolic compound primarily found in blueberries. The antitumor activity of PTE was examined by using the Cell Counting Kit-8, apoptosis assays, cell cycle analysis, JC-1 mitochondrial membrane potential assay, western blot analysis, and tumor xenograft models. PTE treatment induced a dose-dependent inhibition of cell proliferation, including the induction of cell apoptosis and cell cycle arrest at the G0/G1 phase. Moreover, the PI3K/Akt/mTOR pathway was downregulated after PTE treatment, which might account for the anti-MCL effects of PTE. Synergistic cytotoxicity was also observed, both in MCL cells and in xenograft mouse models, when PTE was administered in combination with bortezomib (BTZ). The antitumor effects of PTE shown in our study provide an innovative option for MCL patients with poor responses to standardized therapy. It is noteworthy that the treatment combining PTE with BTZ warrants clinical investigation, which may offer an alternative and effective MCL treatment in the future.

Occurrence, Bioavailability, Anti-inflammatory, and Anticancer Effects of Pterostilbene

“…113 Pterostilbene is found to downregulate the PI3K/Akt/mTOR signaling pathway induction of mantle cell lymphoma JeKo-1 and the Granta-519 cell line apoptosis and cell cycle arrest at the G0/G1 phase. 114 Additionally Chen et al indicate that pterostilbene, via the inhibition of the EGFR/PI3K/Akt/ERK/mTOR signaling pathway, decreases urethane-induced lung tumorigenesis. 59 Moreover, a study has shown that pterostilbene can upregulate a cell-intrinsic checkpoint and repair response protein p53, p21, p27, and p16 expression as well as downregulate the cyclin-dependent kinase levels of cyclin A, cyclin E, Cdk2, Cdk4, and Cdk6, which are associated with Rb phosphorylation, resulting in HL-60 gastric carcinoma cell G1 arrest.…”

Increased mTOR activation in idiopathic multicentric Castleman disease

“…mTOR-Is are effective at inhibiting lymphoproliferation, vascular endothelial growth factor production, and disease symptoms. [21][22][23] Based on our preliminary data in 3 patients 11 and mTOR's role in other lymphoproliferative diseases, [24][25][26][27][28][29][30][31][32] we hypothesized that mTOR signaling is dysregulated in iMCD and a candidate drug target.…”

Connective tissue growth factor promotes cell‐to‐cell communication in human periodontal ligament stem cells via MAPK and PI3K pathway

“…44 Moreover, nuclear Akt signaling plays vital roles in cell proliferation, differentiation, cell cycle, mRNA processing, and exportation, and DNA repair. 45 Akt phosphorylated CREB on serine 133 and triggered transcription of Cx43, which may be another potential mechanism regulating Cx43 expression induced by CTGF. Second, LY294002-treated cells showed a short half-life of Cx43 mRNA.…”

“…The activated MAPK pathway enhances the expression of transcription factors including activator protein‐1 (AP1) or cyclic adenosine monophosphate (cAMP) response element‐binding protein (CREB) in the nucleus, which is bound to the region of the Cx43 promoter, then causing a significant increase of Cx43 expression 44 . Moreover, nuclear Akt signaling plays vital roles in cell proliferation, differentiation, cell cycle, mRNA processing, and exportation, and DNA repair 45 . Akt phosphorylated CREB on serine 133 and triggered transcription of Cx43, which may be another potential mechanism regulating Cx43 expression induced by CTGF.…”