Studies on Antitumor Activity of Squalene and Its Related Compounds

Ikekawa, Tetsuro; Umeji, Mari; Manabe, Takahiko; Yanoma, Syunsuke; Irinoda, Kazuhiko; Mizunuma, H; Ikekawa, Nobuo

doi:10.1248/yakushi1947.106.7_578

Cited by 17 publications

(5 citation statements)

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“…Exogenous Supplementation of Squalene and Related Probes. Exogeneous supplementation of squalene was performed as described previously (56,57), with minor modifications. Squalene and related probes were dissolved in a 1% solution of Tween 20 in DMSO to make 100× stock solutions.…”

Section: Methodsmentioning

confidence: 99%

A key mammalian cholesterol synthesis enzyme, squalene monooxygenase, is allosterically stabilized by its substrate

Yoshioka

Coates

Chua

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Cholesterol biosynthesis is a high-cost process and, therefore, tightly regulated by both transcriptional and posttranslational negative feedback mechanisms in response to the level of cellular cholesterol. Squalene monooxygenase (SM, also known as squalene epoxidase or SQLE) is a rate-limiting enzyme in the cholesterol biosynthetic pathway and catalyzes epoxidation of squalene. The stability of SM is negatively regulated by cholesterol via its N-terminal regulatory domain (SM-N100). In this study, using a SM-luciferase fusion reporter cell line, we performed a chemical genetics screen that identified inhibitors of SM itself as up-regulators of SM. This effect was mediated through the SM-N100 region, competed with cholesterol-accelerated degradation, and required the E3 ubiquitin ligase MARCH6. However, up-regulation was not observed with statins, well-established cholesterol biosynthesis inhibitors, and this pointed to the presence of another mechanism other than reduced cholesterol synthesis. Further analyses revealed that squalene accumulation upon treatment with the SM inhibitor was responsible for the up-regulatory effect. Using photoaffinity labeling, we demonstrated that squalene directly bound to the N100 region, thereby reducing interaction with and ubiquitination by MARCH6. Our findings suggest that SM senses squalene via its N100 domain to increase its metabolic capacity, highlighting squalene as a feedforward factor for the cholesterol biosynthetic pathway.

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Section: Methodsmentioning

confidence: 99%

A key mammalian cholesterol synthesis enzyme, squalene monooxygenase, is allosterically stabilized by its substrate

Yoshioka

Coates

Chua

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Other studies on the antitumor activity of squalene have been reported in Japan. [24][25][26] In our published studies, by ourselves or in collaboration with others, the purpose was to demonstrate whether squalene given orally would have an inhibitory effect on tumors of internal organs. We demonstrated potent inhibition of aberrant hyperproliferation in a mammary epithelial cell line in vitro.…”

Section: Squalene As a Tumor Inhibitormentioning

confidence: 99%

Squalene, Olive Oil, and Cancer Risk: Review and Hypothesis

Newmark

1999

Annals of the New York Academy of Sciences

196

197

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Epidemiologic studies of breast and pancreatic cancer in several Mediterranean populations have demonstrated that increased dietary intake of olive oil is associated with a small decreased risk, or no increased risk, of cancer, despite a high overall lipid intake. Experimental animal models in high dietary fat and cancer also indicate that olive oil either has no effect, or a protective effect, on the prevention of a variety of chemically induced tumors. As a working hypothesis, it is proposed that the high squalene content of olive oil, as compared to other human foods, is a major factor in the cancer-risk reducing effect of olive oil. Experiments in animal models suggest a tumor-inhibiting role for squalene. A mechanism is proposed for the tumor-inhibitory activity of squalene based on its known strong inhibitory activity of HMG-COA reductase catalytic activity in vivo, thus reducing farnesyl pyrophosphate (FPP) availability for "prenylation" of ras oncogene, which relocates this oncogene to cell membranes and is required for the signal-transducing function of ras. Reduction of mutated ras oncogene activation may be useful in breast and colon cancer and may be particularly applicable to pancreatic cancers that are strongly associated with ras oncogenes.

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“…Squalene from shark liver is a popular folk medicine for chronic diseases of the liver (14,15). Antitumor and anticarcinoma activities of squalene have also been reported (16). The traditional source for squalene is primarily from shark and whale liver oil (11,12).…”

Section: Introductionmentioning

confidence: 96%

Squalene Content and Antioxidant Activity of Terminalia catappa Leaves and Seeds

Weng

Chiou

2002

J. Agric. Food Chem.

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Squalene was identified by gas chromatography-mass spectrometry and high-performance liquid chromatography (HPLC) spiking analyses in the supercritical CO(2) extracts of freeze-dried abscisic leaves of Terminalia catappa L. When the freeze-dried abscisic, senescent, mature, and immature leaves and seeds were subjected to supercritical CO(2) extraction at 40 degrees C and 3000 psi and HPLC quantitation, squalene contents were 12.29, 2.42, 1.75, 0.9, and 0% in the extracts and corresponding to 1499, 451, 210, 65, and 0 microg/g in the freeze-dried sample, respectively. When the extracts were applied for antioxidative characterization by supplementation in an iron/ascorbate system with linoleic acid and in a pork fat storage system for inhibition of conjugated diene hydroperoxide (CDHP) formation or in a free radical scavenging system with 1,1-diphenyl-2-picryl-hydrazyl (DPPH), the extracts of leaves exhibited potent antioxidative and DPPH scavenging activities and increased with an increase of leaf maturity. However, the seed extracts only exhibited potent inhibition of CDHP formation and very low DPPH scavenging activity.

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Studies on Antitumor Activity of Squalene and Its Related Compounds

Cited by 17 publications

References 0 publications

A key mammalian cholesterol synthesis enzyme, squalene monooxygenase, is allosterically stabilized by its substrate

A key mammalian cholesterol synthesis enzyme, squalene monooxygenase, is allosterically stabilized by its substrate

Squalene, Olive Oil, and Cancer Risk: Review and Hypothesis

Squalene Content and Antioxidant Activity of Terminalia catappa Leaves and Seeds

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