2-Hydroxypropyl-β-cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum Stress

Zhao, Yiyang; He, Linkang; Zhu, Lingjun; Yan, Nianlong

doi:10.3390/metabo11080562

Cited by 8 publications

(5 citation statements)

References 50 publications

(77 reference statements)

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“…A study conducted in 2017 indicated that in cholesterol-loaded cells, HPβCD had the potential to expand the active cholesterol pool, being the first study documenting that SREBP1 levels were reduced following HPβCD treatment [56]. Contrary to this, in MDA-MB-231 cells, a dose-dependent increase in the expression of HMGCR is reported, with reduced expression of cholesterol efflux proteins ABCA1 and ABCG1 following treatment with HPβCD [57]. This consequently necessitates further mechanistic investigations pertaining to exactly how HPβCD modifies the cellular cholesterol composition in various cancer cell types.…”

Section: Discussionmentioning

confidence: 99%

2-Hydroxypropyl-β-cyclodextrin (HPβCD) as a Potential Therapeutic Agent for Breast Cancer

Saha

Abdulla

Zininga

et al. 2023

Cancers

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Cholesterol accumulation is documented in various malignancies including breast cancer. Consequently, depleting cholesterol in cancer cells can serve as a viable treatment strategy. We identified the potency of 2-hydroxypropyl-β-cyclodextrin (HPβCD), a cholesterol-depletor in vitro against two breast cancer cell lines: MCF-7 (Oestrogen-receptor positive, ER+) and MDA-MB-231 (Triple negative breast cancer (TNBC)). The results were then compared against two non-cancerous cell lines using cytotoxic-, apoptosis-, and cholesterol-based assays. Treatment with HPβCD showed preferential and significant cytotoxic potential in cancer cells, inducing apoptosis in both cancer cell lines (p < 0.001). This was mediated due to significant depletion of cholesterol (p < 0.001). We further tested HPβCD in a MF-1 mice (n = 14) xenograft model and obtained 73.9%, 94% and 100% reduction in tumour size for late-, intermediate-, and early-stage TNBC, respectively. We also detected molecular-level perturbations in the expression patterns of several genes linked to breast cancer and cholesterol signalling pathways using RT2-PCR arrays and have identified SFRP1 as a direct binding partner to HPβCD through SPR drug interaction analysis. This work unravels mechanistic insights into HPβCD-induced cholesterol depletion, which leads to intrinsic apoptosis induction. Results from this study potentiate employing cholesterol depletion as a promising unconventional anticancer therapeutic strategy, which warrants future clinical investigations.

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Section: Discussionmentioning

confidence: 99%

2-Hydroxypropyl-β-cyclodextrin (HPβCD) as a Potential Therapeutic Agent for Breast Cancer

Saha

Abdulla

Zininga

et al. 2023

Cancers

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“…Moreover, our previous study indicated that the activating LXRα, which promoted cholesterol efflux by augmenting ABCA1 and ABCG1 expressions, could significantly reverse tunicamycin-induced ER stress in hepatocytes and macrophages [ 20 ]. Moreover, cholesterol homeostasis was also revealed to modulate the epithelial–mesenchymal transition (EMT) by regulating the ER stress in breast cancer cells [ 33 ]. Furthermore, in the occurrence of ED and cardiovascular disturbances, ER stress is a critical mechanism of ED [ 23 , 26 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

The Effect of Cholesterol Efflux on Endothelial Dysfunction Caused by Oxidative Stress

Liu

Wang

et al. 2023

IJMS

Self Cite

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Endothelial dysfunction (ED) is the initiation of atherosclerosis (AS). Our previous studies have found that cholesterol metabolism and the Wnt/β-catenin pathway can affect endoplasmic reticulum stress (ER stress), which ultimately leads to ED. However, the effects of cholesterol efflux on ED, which are caused by oxidative stress and the correlation among ER stress, Wnt/β-catenin pathway, and cholesterol efflux, are not clear during ED. To uncover them, the expressions of liver X receptors (LXRα and LXRβ) and ATP-binding cassette protein A1 (ABCA1) and G1 (ABCG1) in HUVECs (human umbilical vein endothelial cells) were measured under oxidative stress. Moreover, HUVECs were treated with LXR-623 (LXR agonist), cholesterol, tunicamycin, and salinomycin alone or together. The results indicated that oxidative stress-induced ED could deregulate the expressions of LXRα and LXRβ and trigger the ER stress and Wnt/β-catenin pathway, resulting thereafter in the accumulation of cholesterol. Furthermore, similar results were shown after treatment with cholesterol; however, the activation of liver X receptor (LXR) could reverse these changes. Furthermore, other results demonstrated that tunicamycin-induced ER stress could stimulate the accumulation of cholesterol and the Wnt/β-catenin pathway, further leading to ED. Inversely, salinomycin could reverse the above effects by deregulating the Wnt/β-catenin pathway. Collectively, our results showed that cholesterol efflux is partly responsible for the oxidative stress-induced ED; in addition, ER stress, the Wnt/β-catenin pathway, and cholesterol metabolism can interact with each other to promote ED.

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“…Cholesterol may be removed from the plasmatic membrane by MβCD, which results in increased cholesterol synthesis and the inhibition of ABCA1-mediated efflux [ 34 ]. Zhao et al also showed that treating MDA-MB-231 cancer cells with 2-hydroxypropyl-β-cyclodextrin leads to the upregulation of cholesterol synthesis and LDLR, as well as reduced ABCA1 expression [ 35 ]. Therefore, cyclodextrins exert similar effects as those observed with HA-atRA or HA-C18:1.…”

Section: Discussionmentioning

confidence: 99%

Retinoic Acid Grafted to Hyaluronic Acid Activates Retinoid Gene Expression and Removes Cholesterol from Cellular Membranes

et al. 2022

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All-trans-retinoic acid (atRA) is a potent ligand that regulates gene expression and is used to treat several skin disorders. Hyaluronic acid (HA) was previously conjugated with atRA (HA-atRA) to obtain a novel amphiphilic compound. HA-atRA forms micelles that incorporate hydrophobic molecules and facilitate their transport through the skin. The aim of this study was to determine the influence of HA-atRA on gene expression in skin cells and to compare it with that of unbound atRA. Gene expression was investigated using microarrays and a luciferase system with a canonical atRA promoter. HA-atRA upregulated gene expression similarly to atRA. However, HA-atRA activated the expression of cholesterol metabolism genes, unlike atRA. Further investigation using HPLC and filipin III staining suggested that the treated cells induced cholesterol synthesis to replenish the cholesterol removed from the cells by HA-atRA. HA modified with oleate (HA-C18:1) removed cholesterol from the cells similarly to HA-atRA, suggesting that the cholesterol removal stemmed from the amphiphilic nature of the two derivatives. HA-atRA induces retinoid signaling. Thus, HA-atRA could be used to treat skin diseases, such as acne and psoriasis, where the combined action of atRA signaling and anti-inflammatory cholesterol removal may be potentially beneficial.

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2-Hydroxypropyl-β-cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum Stress

Cited by 8 publications

References 50 publications

2-Hydroxypropyl-β-cyclodextrin (HPβCD) as a Potential Therapeutic Agent for Breast Cancer

2-Hydroxypropyl-β-cyclodextrin (HPβCD) as a Potential Therapeutic Agent for Breast Cancer

The Effect of Cholesterol Efflux on Endothelial Dysfunction Caused by Oxidative Stress

Retinoic Acid Grafted to Hyaluronic Acid Activates Retinoid Gene Expression and Removes Cholesterol from Cellular Membranes

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