Candidate Antimetastasis Drugs Suppress the Metastatic Capacity of Breast Cancer Cells by Reducing Membrane Fluidity

Abstract

Despite the high mortality from metastatic cancer, therapeutic targets to prevent metastasis are limited. Efforts to identify genetic aberrations that predispose tumors to metastasis have been mostly unsuccessful. To understand the nature of candidate targets for metastatic disease, we performed an in silico screen to identify drugs that can inhibit a gene expression signature associated with epithelial-mesenchymal transition (EMT). Compounds discovered through this method, including those previously identified, appeared to restrict metastatic capacity through a common mechanism, the ability to modulate the fluidity of cell membranes. Treatment of breast cancer cell lines with the putative antimetastasis agents reduced membrane fluidity, resulting in decreased cell motility, stem celllike properties, and EMT in vitro, and the drugs also inhibited spontaneous metastasis in vivo. When fluidity was unchanged, the antimetastasis compounds could no longer restrict metastasis, indicating a causal association between fluidity and metastasis. We further demonstrate that fluidity can be regulated by cellular cholesterol flux, as the cholesterol efflux channel ABCA1 potentiated metastatic behaviors in vitro and in vivo. The requirement for fluidity was further supported by the finding in breast cancer patients that ABCA1 was overexpressed in 41% of metastatic tumors, reducing time to metastasis by 9 years. Collectively, our findings reveal increased membrane fluidity as a necessary cellular feature of metastatic potential that can be controlled by many currently available drugs, offering a viable therapeutic opportunity to prevent cancer metastasis.

Targeting the Metabolic Reprogramming That Controls Epithelial-to-Mesenchymal Transition in Aggressive Tumors

“…In keeping, the treatment of breast cancer cell lines with some of these anti-metastatic agents (i.e., alprostadil, amitriptyline, haloperidol, and maprotiline, as well as, salinomycin and thioridazine) reduced membrane fluidity, resulting in EMT impairment, decreased cell motility, and stem cell-like properties, culminating in the impairment of spontaneous metastasis in animal models, thus validating the in silico analysis. The impact of fluidity on the metastatic behavior and the strict correlation between membrane fluidity and cholesterol content was further supported by the finding that in breast cancer patients, the overexpression of the cholesterol efflux channel ABCA1 was associated with increased metastatic success and was revealed in 41% of metastatic tumors (173). …”

“…A fascinating study has recently identified, using an in silico drug screening, a series of pharmacological compounds that can repress the metastatic phenotype of cancer cells by inhibiting a gene expression signature associated with EMT. The compounds discovered using this analysis, including previously acknowledged anti-metastatic drugs, appeared to restrict the metastatic capacity through a common mechanism, i.e., the ability to modulate the fluidity of cell membranes (173). In keeping, the treatment of breast cancer cell lines with some of these anti-metastatic agents (i.e., alprostadil, amitriptyline, haloperidol, and maprotiline, as well as, salinomycin and thioridazine) reduced membrane fluidity, resulting in EMT impairment, decreased cell motility, and stem cell-like properties, culminating in the impairment of spontaneous metastasis in animal models, thus validating the in silico analysis.…”

Runx1 Role in Epithelial and Cancer Cell Proliferation Implicates Lipid Metabolism and Scd1 and Soat1 Activity

“…Membrane organization may in principle control different signaling outcomes (22, 76) although direct evidence for this model is scarce. Previously we linked Runx1 in the skin epithelium and cultured keratinocytes with increased Wnt signaling (28), a pathway important for epithelial cell proliferation (77), and for carcinogenesis (78).…”

“…In addition to normal development and adult homeostasis, cell-intrinsic lipid metabolism plays an important role in various diseases such as stroke, diabetes, inflammation, and most importantly cancer (19–22). It is well established that de novo synthesis of lipids, including fatty acids, occurs in numerous cancers (23).…”

Expression analysis and clinical significance of eIF4E, VEGF-C, E-cadherin and MMP-2 in colorectal adenocarcinoma

“…Transwell migration assay in CRC was performed following the protocol of Chang Lab with slight modification [33]. 2.5×10 5 SW480 cells were seeded in 500 μM starvation medium (0.1% FBS) onto the upper chamber of a Thinsert Cell Culture Insert (Greiner Bio-One #665638) in a 12-well plate.…”