10-Gingerol Targets Lipid Rafts Associated PI3K/Akt Signaling in Radio-Resistant Triple Negative Breast Cancer Cells

Abstract

<jats:p>10-gingerol is a major phenolic lipid found in the rhizomes of ginger (Zingiber officinale). Being amphiphilic in nature, phenolic lipids have the ability to incorporate into cell membranes and modulate membrane properties. The purpose of the present study was to evaluate the effects of 10-gingerol on lipid raft/membrane raft modulation in radio-resistant triple negative breast cancer (MDA-MB-231/IR) cells. The effects of 10-gingerol on MDA-MB-231/IR cells’ proliferation, clonogenic growth, migration, and invasion were assayed using MTT, colony formation, cell migration, and invasion assays, respectively. Sucrose density gradient centrifugation was used to extract lipid rafts. Western blotting and immunofluorescence were employed to assess the effects of 10-gingerol on lipid raft/membrane raft modulation and lipid rafts-associated PI3K/Akt signaling. Cholesterol measurements were carried out using a commercially available kit. 10-gingerol suppressed the proliferation, migration, invasion, and induced apoptosis through targeting the PI3K/Akt signaling pathway in MDA-MB-231/IR cells. Moreover, 10-gingerol was found to modulate the lipid rafts of MDA-MB-231/IR cells and attenuate the key PI3K/Akt signaling components in lipid rafts. The cholesterol content of the lipid rafts and rafts-resident Akt signaling were also affected by exposure to 10-gingerol. The results of the present study highlight rafts-associated PI3K/Akt signaling as a new target of 10-gingerol in MDA-MB-231/IR cells, thus rationalizing a new rafts-mediated treatment approach for radio-resistant triple negative breast cancer cells.</jats:p>

Exploring the molecular targets and mechanisms of [10]-Gingerol for treating triple-negative breast cancer using bioinformatics approaches, molecular docking, and in vivo experiments

“…Moreover, [10]-Gingerol has been reported to exhibit anti-tumor activity by inducing apoptosis through the MAPK pathway in HCT116 human colon cancer cells (18). Gingerol has been subsequently shown to induce apoptosis in a variety of cancer cell types (17,(28)(29)(30). In this study, [10]-Gingerol induced apoptosis by activating the caspasefamily proteins (Caspase-3, Caspase-7, and Caspase-8).…”

Sesquiterpene Alcohol Cedrol Chemosensitizes Human Cancer Cells and Suppresses Cell Proliferation by Destabilizing Plasma Membrane Lipid Rafts

“…Recently, 10-gingerol (C 21 H 34 O 4 ), a β-hydroxy ketone and a phenolic member of monomethoxybenzene, was found to modulate the lipid rafts of breast cancer MDA-MB-231/IR cells. It caused the redistribution of cholesterol content of the lipid rafts and rafts and attenuated the key PI3K/Akt signaling components in lipid rafts of cells ( Ediriweera et al, 2020 ). Another gingerol derivative (6-gingerol) was shown to modulate a variety of classical signaling cascades in different types of cancers especially ERK, JNK, PI3-K/Akt, PLC-γ1, and JAK/STAT pathways ( de Lima et al, 2018 ).…”

Lipid raft involvement in signal transduction in cancer cell survival, cell death and metastasis

“…Therefore, PTEN deficiency is one of the most common types of aberrations in cancer, and its effect is particularly significant in glioblastoma and prostate cancer. 59 Ediriweera et al 60 showed that 10‐gingerol, a natural phenolic lipid, can bind to cell membranes and regulate membrane properties and thus affect the PI3K/Akt signalling pathway in radiation‐resistant triple‐negative breast cancer (MDA‐MB‐231‐IR) cells by regulating lipid raft formation, thereby inhibiting the proliferation, migration and invasion of cancer cells and inducing apoptosis. This process is mainly caused by the entry of amphiphilic 10‐gingerol into the plasma membrane of cancer cells and the transfer of caveolin from the lipid raft to the membrane outside the lipid raft, destroying the lipid raft.…”