Anti-cancer effect of doxorubicin is mediated by downregulation of HMG-Co A reductase via inhibition of EGFR/Src pathway

Yun, Un Jung; Lee, Ji Hye; Shim, Ju Hyun; Yoon, Kyungsil; Goh, Sung‐Ho; Yi, Eun Hee; Ye, Sang Kyu; Lee, Jae Seon; Lee, Hyunji; Park, Jongsun; Lee, In Hye; Kim, Yong Nyun

doi:10.1038/s41374-019-0193-1

Cited by 36 publications

(31 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As shown in Figure 14, all of the examined breast cancer cell lines exhibited an increase in the resistance to the 4-OH-tamoxifen or doxorubicin, confirming that cholesterol and mevalonate induce chemotherapy resistance in breast cancer cells. The observed doxorubicin resistance finds validation in a previous report, which linked the antitumor effect of doxorubicin to its inhibitory effect on the HMGCR function [52]. Moreover, to confirm the close correlation between drug resistance induced by cholesterol and mevalonate through both ERRα and related pathway activation, we performed the same experiment in the presence of XCT790.…”

Section: Mevalonate and Cholesterol Induce Chemotherapy Drug Resistancesupporting

confidence: 74%

Cholesterol and Mevalonate: Two Metabolites Involved in Breast Cancer Progression and Drug Resistance through the ERRα Pathway

Brindisi

Fiorillo

Frattaruolo

et al. 2020

Cells

View full text Add to dashboard Cite

Breast cancer is the second greatest cause of cancer-related death in women. Resistance to endocrine treatments or chemotherapy is a limiting drawback. In this context, this work aims to evaluate the effects of cholesterol and mevalonate during tumor progression and their contribution in the onset of resistance to clinical treatments in use today. In this study, we demonstrated that cholesterol and mevalonate treatments were able to activate the estrogen-related receptor alpha (ERRα) pathway, increasing the expression levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), ERbB2/human epithelial receptor (HER2), tumor protein D52 (TPD52), and NOTCH2 proteins in breast cancer cells. The activation of this pathway is shown to be responsible for intense metabolic switching, higher proliferation rates, sustained motility, the propagation of cancer stem-like cells (CSCs), and lipid droplet formation. All of these events are related to greater tumor propagation, aggressiveness, and drug resistance. Furthermore, the activation and expression of proteins induced by the treatment with cholesterol or mevalonate are consistent with those obtained from the MCF-7/TAMr cell line, which is largely used as a breast cancer model of acquired endocrine therapy resistance. Altogether, our data indicate that cholesterol and mevalonate are two metabolites implicated in breast cancer progression, aggressiveness, and drug resistance, through the activation of the ERRα pathway. Our findings enable us to identify the ERRα receptor as a poor prognostic marker in patients with breast carcinoma, suggesting the correlation between cholesterol/mevalonate and ERRα as a new possible target in breast cancer treatment.

show abstract

Section: Mevalonate and Cholesterol Induce Chemotherapy Drug Resistancesupporting

confidence: 74%

Cholesterol and Mevalonate: Two Metabolites Involved in Breast Cancer Progression and Drug Resistance through the ERRα Pathway

Brindisi

Fiorillo

Frattaruolo

et al. 2020

Cells

View full text Add to dashboard Cite

show abstract

“…According with this, it has been suggested that several anticancer drugs may have anti-proliferative function, limiting the content or production of cholesterol. For instance, it has been shown that doxorubicin caused the death of cancer cells by promoting a reduction in HMGCR levels and causing a decrease in cholesterol content (Yun et al, 2019). Other data displayed that tamoxifen modulated cholesterol metabolism in breast cancer cells (Segala et al, 2013).…”

Section: Targeting Cholesterol Pathways As Cancer Therapymentioning

confidence: 99%

Role of Cholesterol and Lipid Rafts in Cancer Signaling: A Promising Therapeutic Opportunity?

Vona

Iessi

Matarrese

2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Cholesterol is a lipid molecule that plays an essential role in a number of biological processes, both physiological and pathological. It is an essential structural constituent of cell membranes, and it is fundamental for biosynthesis, integrity, and functions of biological membranes, including membrane trafficking and signaling. Moreover, cholesterol is the major lipid component of lipid rafts, a sort of lipid-based structures that regulate the assembly and functioning of numerous cell signaling pathways, including those related to cancer, such as tumor cell growth, adhesion, migration, invasion, and apoptosis. Considering the importance of cholesterol metabolism, its homeostasis is strictly regulated at every stage: import, synthesis, export, metabolism, and storage. The alterations of this homeostatic balance are known to be associated with cardiovascular diseases and atherosclerosis, but mounting evidence also connects these behaviors to increased cancer risks. Although there is conflicting evidence on the role of cholesterol in cancer development, most of the studies consistently suggest that a dysregulation of cholesterol homeostasis could lead to cancer development. This review aims to discuss the current understanding of cholesterol homeostasis in normal and cancerous cells, summarizing key findings from recent preclinical and clinical studies that have investigated the role of major players in cholesterol regulation and the organization of lipid rafts, which could represent promising therapeutic targets.

show abstract

“…In cardiomyocytes, DOX also upregulates oxysterols and hence elicits LXR activation 34 . On the other hand, other studies report downregulation of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) in epidermal and prostate cancer cell lines 35 . Furthermore, chemotherapy may modify the cholesterol efflux from the environment of the cell, which could affect the cholesterol content in many cellular compartments 36 .…”

Section: Regulation Of the De Novo Lipogenesis Of Fatty Acids Glycermentioning

confidence: 99%

Anthracyclins increase free PUFAs and etherPEs with PUFAs as potential hallmarks of lipid peroxidation and ferroptosis

Balgoma

Kullenberg

Calitz

et al. 2021

Preprint

View full text Add to dashboard Cite

Metabolic and personalized interventions in cancer treatment require a better under-standing of the relationship between the induction of cell death and metabolism. Consequently, we treated three primary liver cancer cell lines with two anthracyclins (doxorubicin and idarubin) and studied the changes of the lipidome. We found that both anthracyclins in the three cell lines increased the levels of polyunsaturated fatty acids (PUFAs) and alkylacylglycerophosphoethano-lamines (etherPEs) with PUFAs. As PUFAs and alkylacylglycerophospholipids with PUFAs are fundamental in lipid peroxidation during ferroptotic cell death, our results suggests supplementa-tion with PUFAs and/or etherPEs with PUFAs as a potential general adjuvant of anthracyclins. In contrast, neither the markers of de novo lipogenesis nor cholesterol lipids presented the same trend in all cell lines and treatments. In agreement with previous research, this suggests that modulation of the metabolism of cholesterol could be considered a specific adjuvant of anthracyclins depend-ing on the type of tumor and the individual. Finally, we discuss the changes in the lipidome in re-lation to the endoplasmic reticulum stress and the sensitivity to anthracyclins of the different cells. In conclusion, our results suggest that the modulation of different lipid metabolic pathways may be considered for generalized and personalized metabochemotherapies.

show abstract

Anti-cancer effect of doxorubicin is mediated by downregulation of HMG-Co A reductase via inhibition of EGFR/Src pathway

Cited by 36 publications

References 52 publications

Cholesterol and Mevalonate: Two Metabolites Involved in Breast Cancer Progression and Drug Resistance through the ERRα Pathway

Cholesterol and Mevalonate: Two Metabolites Involved in Breast Cancer Progression and Drug Resistance through the ERRα Pathway

Role of Cholesterol and Lipid Rafts in Cancer Signaling: A Promising Therapeutic Opportunity?

Anthracyclins increase free PUFAs and etherPEs with PUFAs as potential hallmarks of lipid peroxidation and ferroptosis

Contact Info

Product

Resources

About