A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition

Mahoney, Christopher E.; Pirman, David; Chubukov, Victor; Sleger, Taryn; Hayes, Sebastian; Fan, Zi Peng; Allen, Eric L.; Chen, Ying; Huang, Lingling; Liu, Meina; Zhang, Yingjia; McDonald, Gabrielle; Narayanaswamy, Rohini; Choe, Sung; Chen, Yue; Größ, Stefan; Cianchetta, Giovanni; Padyana, Anil K.; Murray, Stuart; Liu, Wei; Marks, Kevin M.; Murtie, Joshua; Dorsch, Marion; Jin, Shengfang; Nagaraja, N.; Biller, Scott A.; Roddy, Thomas P.; Popovici‐Muller, Janeta; Smolen, Gromoslaw A.

doi:10.1038/s41467-018-07959-4

Cited by 65 publications

(72 citation statements)

References 49 publications

(39 reference statements)

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“…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

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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

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Section: Discussionmentioning

confidence: 88%

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

et al. 2020

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“…Consistent with a role for SM in adaptation to hypoxic stress, NB-598 treatment greatly increases the susceptibility of breast and colorectal cancer cells to hypoxia-induced cell death (51). Recently, squalene accumulation has been noted in lymphoma and neuroendocrine cancer cells (34,35). The metabolic vulnerability resulting from SM inhibition in neuroendocrine cancer cells is due to toxic squalene accumulation (34).…”

Section: Squalenementioning

confidence: 84%

“…This work provides mechanistic insights into the regulation of human SM, an essential rate-limiting enzyme of cholesterol synthesis that is implicated in disease (32)(33)(34)(35). The substrate of SM, squalene, is known to bind to the catalytic domain of SM.…”

Section: Discussionmentioning

confidence: 99%

“…Although the association of SM with lipid droplets has been reported, as has the accumulation of squalene in these compartments (28,34,38), we excluded a role for lipid droplet dynamics in squalene-mediated stabilization within our HEK293 cell models, which do not actively synthesize lipid droplets. In other cell types that produce a larger amount of lipid droplets, such as adipocytes, there may exist a cell type-or organ-specific role for squalene-lipid droplet dynamics in the regulation of SM proteostasis, offering an interesting area for further study.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, squalene accumulation has been noted in lymphoma and neuroendocrine cancer cells (34,35). The metabolic vulnerability resulting from SM inhibition in neuroendocrine cancer cells is due to toxic squalene accumulation (34). Of note, a subset of neuroendocrine cancer cells lack sensitivity to SM inhibition as these cells could sequester toxic squalene.…”

Section: Squalenementioning

confidence: 99%

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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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Targeting Squalene Epoxidase Confers Metabolic Vulnerability and Overcomes Chemoresistance in HNSCC

et al. 2023

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Cisplatin resistance poses a substantial hurdle in effectively treating head and neck squamous cell carcinoma (HNSCC). Utilizing multiple tumor models and examining an internal HNSCC cohort, squalene epoxidase (SQLE) is pinpointed as a key driver of chemoresistance and tumorigenesis, operating through a cholesterol‐dependent pathway. Comprehensive transcriptomic analysis reveals that SQLE is essential for maintaining c‐Myc transcriptional activity by stabilizing the c‐Myc protein and averting its ubiquitin‐mediated degradation. Mechanistic investigation demonstrates that SQLE inhibition diminishes Akt's binding affinity to lipid rafts via a cholesterol‐dependent process, subsequently deactivating lipid raft‐localized Akt, reducing GSK‐3β phosphorylation at S9, and increasing c‐Myc phosphorylation at T58, ultimately leading to c‐Myc destabilization. Importantly, employing an Sqle conditional knockout mouse model, SQLE's critical role in HNSCC initiation and progression is established. The preclinical findings demonstrate the potent synergistic effects of combining terbinafine and cisplatin in arresting tumor growth. These discoveries not only provide novel insights into the underlying mechanisms of SQLE‐mediated cisplatin resistance and tumorigenesis in HNSCC but also propose a promising therapeutic avenue for HNSCC patients unresponsive to conventional cisplatin‐based chemotherapy.

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A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition

Cited by 65 publications

References 49 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

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

Targeting Squalene Epoxidase Confers Metabolic Vulnerability and Overcomes Chemoresistance in HNSCC

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