Involvement of the PI3K/Akt/Nrf2 Signaling Pathway in Resveratrol-Mediated Reversal of Drug Resistance in HL-60/ADR Cells

Li, Yongjun; Guo, Yukai; Zhuang, Feng; Bergan, Raymond C.; Li, Bo; Qin, Yong-Liang; Zhao, Lianmei; Zhang, Zhenzhen; Shi, Min

doi:10.1080/01635581.2019.1578387

Cited by 39 publications

(22 citation statements)

References 27 publications

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“…In fact, NRF2 and RNA Polymerase II were recruited to the PIR promoter, in the presence of E7; however, other intermediaries related to Pirin upregulation maybe involved. Previously, it has been reported that the PI3K/AKT1 pathway regulates NRF2 levels through glycogen synthase kinase 3 beta (GSK3B) phosphorylation [ 54 , 55 , 56 ] for subsequent NRF2 release from the GSK3B–CULIN3 complex, targeting it for proteasome-mediated degradation [ 57 ]. Thus, by increasing the PI3K/AKT1 pathway activation by HPV16 E7, correspondingly, NRF2 levels are expected to increase.…”

Section: Discussionmentioning

confidence: 99%

Human Papillomavirus 16 E7 Promotes EGFR/PI3K/AKT1/NRF2 Signaling Pathway Contributing to PIR/NF-κB Activation in Oral Cancer Cells

Carrillo-Beltrán

Muñoz

Guerrero-Vásquez

et al. 2020

Cancers

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A subset of oral carcinomas is etiologically related to high-risk human papillomavirus (HR-HPV) infection, with HPV16 being the most frequent HR-HPV type found in these carcinomas. The oncogenic role of HR-HPV is strongly dependent on the overexpression of E6 and E7 oncoproteins, which, in turn, induce p53 and pRb degradation, respectively. Additionally, it has been suggested that HR-HPV oncoproteins are involved in the regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inducing cancer progression and metastasis. Previously, we reported that HPV16 E7 oncoprotein promotes Pirin upregulation resulting in increased epithelial–mesenchymal transition (EMT) and cell migration, with Pirin being an oxidative stress sensor and activator of NF-κB. In this study, we demonstrate the mechanism by which HPV16 E7-mediated Pirin overexpression occurs by promoting EGFR/PI3K/AKT1/NRF2 signaling, thus causing PIR/NF-κB activation in oral tumor cells. Our results demonstrate a new mechanism by which E7 contributes to oral cancer progression, proposing PIR as a potential new therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Human Papillomavirus 16 E7 Promotes EGFR/PI3K/AKT1/NRF2 Signaling Pathway Contributing to PIR/NF-κB Activation in Oral Cancer Cells

Carrillo-Beltrán

Muñoz

Guerrero-Vásquez

et al. 2020

Cancers

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“…These convincing results suggested that the PI3K/AKT/Nrf2 pathway stimulated MRP1 and participated in the reversal of VP-mediated MDR cancer 113 . The PI3K/AKT signaling pathway inhibitor LY294002 blocked the drug transport of HT29RDB overexpressing MRP1 protein in colon cancer cells 114 . Therefore, the transport activities of P-gp and MRP1 may have a common regulatory mechanism involved in the PI3K/AKT pathway, and their inhibitors similarly affected resistance based on P-gp and MRP1 115 .…”

Section: Mrp1mentioning

confidence: 95%

PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers

et al. 2020

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Multidrug resistance (MDR) is the dominant challenge in the failure of chemotherapy in cancers. Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that spreads intracellular signal cascades and regulates a variety of cellular processes. PI3Ks are considered significant causes of chemoresistance in cancer therapy. Protein kinase B (AKT) is also a significant downstream effecter of PI3K signaling, and it modulates several pathways, including inhibition of apoptosis, stimulation of cell growth, and modulation of cellular metabolism. This review highlights the aberrant activation of PI3K/AKT as a key link that modulates MDR. We summarize the regulation of numerous major targets correlated with the PI3K/AKT pathway, which is further related to MDR, including the expression of apoptosis-related protein, ABC transport and glycogen synthase kinase-3 beta (GSK-3β), synergism with nuclear factor kappa beta (NF-κB) and mammalian target of rapamycin (mTOR), and the regulation of glycolysis.

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“…Phytochemicals, which are natural compounds from plants, have been recognized as vital resources for novel drugs (5). For example, curcumin (6), epigallocatechin gallate (EGCG) (7), genistein (8) and resveratrol (9) have been reported to possess anti-AML properties. Curcumin is the main polyphenol component extracted from rhizomes of the plant Curcuma longa, and its therapeutic benefit has been demonstrated in various cancer types, including AML (10).…”

Section: Introductionmentioning

confidence: 99%

Curcumin promotes cell cycle arrest and apoptosis of acute myeloid leukemia cells by inactivating AKT

et al. 2021

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Curcumin, a phytochemical from rhizomes of the plant Curcuma longa , has been reported to exert potential anticancer properties in various cancer types, including acute myeloid leukemia (AML). However, the underlying mechanism remains poorly understood. The present study demonstrated that curcumin had a stronger cytotoxic activity against AML cells compared with three other types of phytochemicals (epigallocatechin gallate, genistein and resveratrol). Protein phosphorylation profiling using an antibody array identified that curcumin treatment increased the phosphorylation levels of 14 proteins and decreased those of four proteins. A protein-protein interaction network was constructed using the STRING database, in which AKT was identified as a hub protein with the highest connectivity (PRAS40, 4E-BP1, P70S6K, RAF-1 and p27). Western blotting results indicated that curcumin dose-dependently suppressed the phosphorylation of AKT, PRAS40, 4E-BP1, P70S6K, RAF-1 and p27 in AML cell lines (ML-2 and OCI-AML5). It was also demonstrated that curcumin regulated the cell cycle- and apoptosis-related proteins (cyclin D1, p21, Bcl2, cleaved-caspase-3 and cleaved-PARP), leading to cell cycle arrest and apoptosis in both ML-2 and OCI-AML5 cells. These effects of curcumin were enhanced by the AKT inhibitor afuresertib but were suppressed by the AKT activator SC-79, indicating that curcumin functions via AKT. In the AML xenograft mouse model, curcumin and afuresertib synergistically suppressed the engraftment, proliferation and survival of AML cells. Collectively, the present study demonstrated that curcumin exerted anti-AML roles by inactivating AKT and these findings may aid in the treatment of AML.

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Involvement of the PI3K/Akt/Nrf2 Signaling Pathway in Resveratrol-Mediated Reversal of Drug Resistance in HL-60/ADR Cells

Cited by 39 publications

References 27 publications

Human Papillomavirus 16 E7 Promotes EGFR/PI3K/AKT1/NRF2 Signaling Pathway Contributing to PIR/NF-κB Activation in Oral Cancer Cells

Human Papillomavirus 16 E7 Promotes EGFR/PI3K/AKT1/NRF2 Signaling Pathway Contributing to PIR/NF-κB Activation in Oral Cancer Cells

PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers

Curcumin promotes cell cycle arrest and apoptosis of acute myeloid leukemia cells by inactivating AKT

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