Cholesterol Is a Regulator of CAV1 Localization and Cell Migration in Oral Squamous Cell Carcinoma

Abstract

Cholesterol plays an important role in cancer progression, as it is utilized in membrane biogenesis and cell signaling. Cholesterol-lowering drugs have exhibited tumor-suppressive effects in oral squamous cell carcinoma (OSCC), suggesting that cholesterol is also essential in OSCC pathogenesis. However, the direct effects of cholesterol on OSCC cells remain unclear. Here, we investigated the role of cholesterol in OSCC with respect to caveolin-1 (CAV1), a cholesterol-binding protein involved in intracellular cholesterol transport. Cholesterol levels in OSCC cell lines were depleted using methyl-β-cyclodextrin and increased using the methyl-β-cyclodextrin-cholesterol complex. Functional analysis was performed using timelapse imaging, and CAV1 expression in cholesterol-manipulated cells was investigated using immunofluorescence and immunoblotting assays. CAV1 immunohistochemistry was performed on surgical OSCC samples. We observed that cholesterol addition induced polarized cell morphology, along with CAV1 localization at the trailing edge, and promoted cell migration. Moreover, CAV1 was upregulated in the lipid rafts and formed aggregates in the plasma membrane in cholesterol-added cells. High membranous CAV1 expression in tissue specimens was associated with OSCC recurrence. Therefore, cholesterol promotes the migration of OSCC cells by regulating cell polarity and CAV1 localization to the lipid raft. Furthermore, membranous CAV1 expression is a potential prognostic marker for OSCC patients.

Exploring the role of cyclodextrins as a cholesterol scavenger: a molecular dynamics investigation of conformational changes and thermodynamics

“…The mechanisms underlying these interactions are still being investigated, but the potential applications of CDs as cholesterol-lowering agents have been demonstrated in preclinical and clinical studies. The use of CDs as cholesterol-lowering agents has the potential to provide a safe and effective alternative to traditional cholesterol-lowering drugs 15 , 16 . The interaction between cholesterol and CDs is primarily driven by the hydrophobic effect, which arises from the tendency of nonpolar molecules to aggregate in aqueous solutions.…”

Differentially Expressed Genes, miRNAs and Network Models: A Strategy to Shed Light on Molecular Interactions Driving HNSCC Tumorigenesis

“…As examples, we have FN1, whose over-expression correlates with the tumorigenesis, prognosis and radioresistance of HNSCC [ 69 ], EPHB2, that induces angiogenesis via the activation of ephrin reverse signaling [ 70 ], or CAV1, typically upregulated and related to the lipid metabolism [ 71 ]. In this context, the upregulation we observed for apolipoproteins (APOs) and fatty acid desaturase (FADS) gene families remarked the role of lipid profiles in HNSCC [ 72 , 73 ]. However, we did not appreciate this for the carbohydrate or glutamine metabolism, as reported in other studies [ 74 ].…”

Statins as anti‐tumor agents: A paradigm for repurposed drugs

“… 120 As statins lead to decreased levels of cholesterol, their action in cancer may result in compromised functionality of tumor cell membranes, thereby impeding tumor growth and metastasis. 121 A recent study proposed cholesterol metabolism as therapeutic target in leukemia, highlighting the impact of atorvastatin on the RORγ/SREBP2 axis. 122 Moreover, in cholesterol‐rich membranes, statins may undergo partitioning into rafts and forming complexes with specific proteins.…”