Squalene epoxidase promotes the proliferation and metastasis of lung squamous cell carcinoma cells though extracellular signal‐regulated kinase signaling

Ge, Hong; Zhao, Yi; Shi, Xinyan; Tan, Zhen; Chi, Xiaorui; He, Min; Jiang, Guohui; Ji, Lixia; Li, Hongmei

doi:10.1111/1759-7714.12944

Cited by 35 publications

(39 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This has previously been shown to occur in response to oxidative stress by helping cells to obtain cystine needed for glutathione production (52). Of note, the statin-mediated effect on ROS through CoQ is distinctly different from recent reports on squalene, which accumulates in some cancers and has an antioxidant function (53,54).…”

Section: Discussionmentioning

confidence: 88%

Targeting the Metabolic Response to Statin-Mediated Oxidative Stress Produces a Synergistic Antitumor Response

et al. 2020

View full text Add to dashboard Cite

Statins are widely prescribed inhibitors of the mevalonate pathway, acting to lower systemic cholesterol levels. The mevalonate pathway is critical for tumorigenesis and is frequently upregulated in cancer. Nonetheless, reported effects of statins on tumor progression are ambiguous, making it unclear whether statins, alone or in combination, can be used for chemotherapy. Here, using advanced mass spectrometry and isotope tracing, we showed that statins only modestly affected cancer cholesterol homeostasis. Instead, they significantly reduced synthesis and levels of another downstream product, the mitochondrial electron carrier coenzyme Q, both in cultured cancer cells and tumors. This compromised oxidative phosphorylation, causing severe oxidative stress. To compensate, cancer cells upregulated antioxidant metabolic pathways, including reductive carboxylation, proline synthesis, and cystine import. Targeting cystine import with an xCT transporterlowering MEK inhibitor, in combination with statins, caused profound tumor cell death. Thus, statin-induced ROS production in cancer cells can be exploited in a combinatorial regimen. Significance: Cancer cells induce specific metabolic pathways to alleviate the increased oxidative stress caused by statin treatment, and targeting one of these pathways synergizes with statins to produce a robust antitumor response. See related commentary by Cordes and Metallo, p. 151

show abstract

Section: Discussionmentioning

confidence: 88%

Targeting the Metabolic Response to Statin-Mediated Oxidative Stress Produces a Synergistic Antitumor Response

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Three key enzymes of the mevalonate pathway, FPPS, SQS and GGPPS, are also associated with stage and metastasis of NSCLC ( 117 – 119 ). Of these enzymes, SQS is increased in invasive lung cancer cells and in the tumor regions of lung cancer specimens, and significantly associated with metastasis and poor prognosis by enhancing NF-κB-mediated up-regulation of matrix metallopeptidase-1 ( 117 ) or modulating extracellular signal-regulated kinase (ERK) signaling ( 120 ). FPPS plays an important role in promoting cell invasion and EMT through the RhoA/ROCK1 pathway ( 118 ).…”

Section: Srebp-2 Signaling and The Enzymes From The Mevalonate Pathwamentioning

confidence: 99%

Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

et al. 2020

View full text Add to dashboard Cite

Recently, targeting metabolic reprogramming has emerged as a potential therapeutic approach for fighting cancer. Sterol regulatory element binding protein-2 (SREBP-2), a basic helix-loop-helix leucine zipper transcription factor, mainly regulates genes involved in cholesterol biosynthesis and homeostasis. SREBP-2 binds to the sterol regulatory elements (SREs) in the promoters of its target genes and activates the transcription of mevalonate pathway genes, such as HMG-CoA reductase (HMGCR), mevalonate kinase and other key enzymes. In this review, we first summarized the structure of SREBP-2 and its activation and regulation by multiple signaling pathways. We then found that SREBP-2 and its regulated enzymes, including HMGCR, FPPS, SQS, and DHCR4 from the mevalonate pathway, participate in the progression of various cancers, including prostate, breast, lung, and hepatocellular cancer, as potential targets. Importantly, preclinical and clinical research demonstrated that fatostatin, statins, and N-BPs targeting SREBP-2, HMGCR, and FPPS, respectively, alone or in combination with other drugs, have been used for the treatment of different cancers. This review summarizes new insights into the critical role of the SREBP-2-regulated mevalonate pathway for cancer and its potential for targeted cancer therapy.

show abstract

“…Consistently, inhibiting SQLE in MCF7 breast cancer cells reduces cell proliferation and ERK phosphorylation/activation (106), which is a key factor involved in initiating cell proliferation and migration in cancer cells (108). ERK phosphorylation and activation has previously been shown to be regulated by SQLE in other cell types including hepatocellular carcinoma cells ( 109) and lung squamous cell carcinoma cells (110). In fact, SQLE-mediated cholesterol synthesis preserves breast cancer stem cell stemness through PI3K/AKT signaling, another proliferative survival pathway, upon stabilization of SQLE mRNA by long non-coding RNA 030 and poly(rC) binding protein 2 (111).…”

Section: Discussionmentioning

confidence: 72%

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

Squalene epoxidase promotes the proliferation and metastasis of lung squamous cell carcinoma cells though extracellular signal‐regulated kinase signaling

Cited by 35 publications

References 23 publications

Targeting the Metabolic Response to Statin-Mediated Oxidative Stress Produces a Synergistic Antitumor Response

Targeting the Metabolic Response to Statin-Mediated Oxidative Stress Produces a Synergistic Antitumor Response

Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

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

Contact Info

Product

Resources

About