Sterol synthesis pathway inhibition as a target for cancer treatment

Feltrin, Sara; Ravera, Francesco; Traversone, Noemi; Ferrando, Lorenzo; Bedognetti, Davide; Ballestrero, Alberto; Zoppoli, Gabriele

doi:10.1016/j.canlet.2020.07.010

Cited by 17 publications

(23 citation statements)

References 94 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Targeting cholesterol biosynthesis and cholesterol esterification has been proposed as a promising therapy for cancer treatment [ 57 ]. Since HMGCR and SQLE are two rate‐limiting enzymes of cholesterol biosynthesis, they attract much attention as potential targets [ 58 ]. SQLE has been found to be upregulated significantly in numerous tumors, such as breast, prostate and liver cancer, with its upregulation being positively correlated with poor prognosis [ 59 , 60 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

Squalene epoxidase promotes colorectal cancer cell proliferation through accumulating calcitriol and activating CYP24A1‐mediated MAPK signaling

Pan

et al. 2021

Cancer Communications

View full text Add to dashboard Cite

Background Colorectal cancer (CRC) is one of the most malignant tumors with high incidence, yet its molecular mechanism is not fully understood, hindering the development of targeted therapy. Metabolic abnormalities are a hallmark of cancer. Targeting dysregulated metabolic features has become an important direction for modern anticancer therapy. In this study, we aimed to identify a new metabolic enzyme that promotes proliferation of CRC and to examine the related molecular mechanisms. Methods We performed RNA sequencing and tissue microarray analyses of human CRC samples to identify new genes involved in CRC. Squalene epoxidase (SQLE) was identified to be highly upregulated in CRC patients. The regulatory function of SQLE in CRC progression and the therapeutic effect of SQLE inhibitors were determined by measuring CRC cell viability, colony and organoid formation, intracellular cholesterol concentration and xenograft tumor growth. The molecular mechanism of SQLE function was explored by combining transcriptome and untargeted metabolomics analysis. Western blotting and real‐time PCR were used to assess MAPK signaling activation by SQLE. Results SQLE‐related control of cholesterol biosynthesis was highly upregulated in CRC patients and associated with poor prognosis. SQLE promoted CRC growth in vitro and in vivo. Inhibition of SQLE reduced the levels of calcitriol (active form of vitamin D3) and CYP24A1, followed by an increase in intracellular Ca2+ concentration. Subsequently, MAPK signaling was suppressed, resulting in the inhibition of CRC cell growth. Consistently, terbinafine, an SQLE inhibitor, suppressed CRC cell proliferation and organoid and xenograft tumor growth. Conclusions Our findings demonstrate that SQLE promotes CRC through the accumulation of calcitriol and stimulation of CYP24A1‐mediated MAPK signaling, highlighting SQLE as a potential therapeutic target for CRC treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Squalene epoxidase promotes colorectal cancer cell proliferation through accumulating calcitriol and activating CYP24A1‐mediated MAPK signaling

Pan

et al. 2021

Cancer Communications

View full text Add to dashboard Cite

show abstract

“…The cholesterol biosynthesis pathway plays a significant role in cellular metabolism as it provides cholesterol and other sterol intermediates required for multiple metabolic pathways associated with sterols [41,51]. Our in silico and metabolite analysis revealed the upregulation of cholesterol biosynthesis in PC, which could explain the high cholesterol levels in the plasma of PC patients, which has been of keen interest in cancer as a potential target [52]. For instance, the upregulation of the rate-limiting enzyme HMGCR inevitably enhances cholesterol synthesis in different malignancies, making it a predictable survival marker and target in malignancies [37].…”

Section: Discussionmentioning

confidence: 77%

Ubiquitous Aberration in Cholesterol Metabolism across Pancreatic Ductal Adenocarcinoma

et al. 2022

View full text Add to dashboard Cite

Pancreatic cancer (PC) is characterized by metabolic deregulations that often manifest as deviations in metabolite levels and aberrations in their corresponding metabolic genes across the clinical specimens and preclinical PC models. Cholesterol is one of the critical metabolites supporting PC, synthesized or acquired by PC cells. Nevertheless, the significance of the de novo cholesterol synthesis pathway has been controversial in PC, indicating the need to reassess this pathway in PC. We utilized preclinical models and clinical specimens of PC patients and cell lines and utilized mass spectrometry-based sterol analysis. Further, we also performed in silico analysis to corroborate the significance of de novo cholesterol synthesis pathway in PC. Our results demonstrated alteration in free sterol levels, including free cholesterol, across in vitro, in vivo, and clinical specimens of PC. Especially, our sterol analyses established consistent alterations in free cholesterol across the different PC models. Overall, this study demonstrates the significance and consistency in deviation of cholesterol synthesis pathway in PC while showing the aberrations in sterol metabolite intermediates and the related genes using preclinical models, in silico platforms, and the clinical specimens.

show abstract

“…association with CLDs and role in metastasis. SQLE catalyzes the epoxidation of squalene and is considered the second rate-limiting step in cholesterol synthesis (103). SQLE localizes to CLDs in yeast cells (104) and has been shown to regulate CLD dynamics.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Characterization of Cytoplasmic Lipid Droplets in Human Metastatic Breast Cancer Cells

et al. 2021

View full text Add to dashboard Cite

One of the characteristic features of metastatic breast cancer is increased cellular storage of neutral lipid in cytoplasmic lipid droplets (CLDs). CLD accumulation is associated with increased cancer aggressiveness, suggesting CLDs contribute to metastasis. However, how CLDs contribute to metastasis is not clear. CLDs are composed of a neutral lipid core, a phospholipid monolayer, and associated proteins. Proteins that associate with CLDs regulate both cellular and CLD metabolism; however, the proteome of CLDs in metastatic breast cancer and how these proteins may contribute to breast cancer progression is unknown. Therefore, the purpose of this study was to identify the proteome and assess the characteristics of CLDs in the MCF10CA1a human metastatic breast cancer cell line. Utilizing shotgun proteomics, we identified over 1500 proteins involved in a variety of cellular processes in the isolated CLD fraction. Interestingly, unlike other cell lines such as adipocytes or enterocytes, the most enriched protein categories were involved in cellular processes outside of lipid metabolism. For example, cell-cell adhesion was the most enriched category of proteins identified, and many of these proteins have been implicated in breast cancer metastasis. In addition, we characterized CLD size and area in MCF10CA1a cells using transmission electron microscopy. Our results provide a hypothesis-generating list of potential players in breast cancer progression and offers a new perspective on the role of CLDs in cancer.

show abstract

Sterol synthesis pathway inhibition as a target for cancer treatment

Cited by 17 publications

References 94 publications

Squalene epoxidase promotes colorectal cancer cell proliferation through accumulating calcitriol and activating CYP24A1‐mediated MAPK signaling

Squalene epoxidase promotes colorectal cancer cell proliferation through accumulating calcitriol and activating CYP24A1‐mediated MAPK signaling

Ubiquitous Aberration in Cholesterol Metabolism across Pancreatic Ductal Adenocarcinoma

Proteomic Characterization of Cytoplasmic Lipid Droplets in Human Metastatic Breast Cancer Cells

Contact Info

Product

Resources

About