Repurposing the Antidepressant Sertraline as SHMT Inhibitor to Suppress Serine/Glycine Synthesis–Addicted Breast Tumor Growth

Geeraerts, Shauni Lien; Kampen, Kim R.; Rinaldi, Gianmarco; Gupta, Purvi; Planque, Mélanie; Louros, Nikolaos; Heylen, Elien; Cremer, Kaat De; Brucker, Klaas De; Vereecke, Stijn; Verbelen, Benno; Vermeersch, Pieter; Schymkowitz, Joost; Rousseau, Frédéric; Cassiman, David; Fendt, Sarah-Maria; Voet, Arnout; Cammue, Bruno P. A.; Thevissen, Karin; Keersmaecker, Kim De

doi:10.1158/1535-7163.mct-20-0480

Cited by 36 publications

(42 citation statements)

References 51 publications

(81 reference statements)

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“…An NAD-competitive PHGDH inhibitor, 15 fragments, reduces cell proliferation in PHGDH -amplified breast cancer cell line (MDA-MB-468) ( Unterlass et al, 2018 ). Sertraline, an antidepressant, is a selective serotonin reuptake inhibitor (SSRI) class ( MacQueen et al, 2001 ), but it also works as a competitive dual SHMT1/2 inhibitor, reducing the cell growth in serine/glycine synthesis-addicted breast cancer cell line (MDA-MB-468) and decreasing the tumor growth in a mouse xenograft study ( Geeraerts et al, 2021b ).…”

Section: Clinical Application Of Glucose Transporters and Glucose Metabolism In Breast Cancermentioning

confidence: 99%

Glucose Metabolism and Glucose Transporters in Breast Cancer

Shin

Koo

2021

Front. Cell Dev. Biol.

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Breast cancer is the most common malignancy in women worldwide and is associated with high mortality rates despite the continuously advancing treatment strategies. Glucose is essential for cancer cell metabolism owing to the Warburg effect. During the process of glucose metabolism, various glycolytic metabolites, such as serine and glycine metabolites, are produced and other metabolic pathways, such as the pentose phosphate pathway (PPP), are associated with the process. Glucose is transported into the cell by glucose transporters, such as GLUT. Breast cancer shows high expressions of glucose metabolism-related enzymes and GLUT, which are also related to breast cancer prognosis. Triple negative breast cancer (TNBC), which is a high-grade breast cancer, is especially dependent on glucose metabolism. Breast cancer also harbors various stromal cells such as cancer-associated fibroblasts and immune cells as tumor microenvironment, and there exists a metabolic interaction between these stromal cells and breast cancer cells as explained by the reverse Warburg effect. Breast cancer is heterogeneous, and, consequently, its metabolic status is also diverse, which is especially affected by the molecular subtype, progression stage, and metastatic site. In this review, we will focus on glucose metabolism and glucose transporters in breast cancer, and we will additionally discuss their potential applications as cancer imaging tracers and treatment targets.

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Section: Clinical Application Of Glucose Transporters and Glucose Metabolism In Breast Cancermentioning

confidence: 99%

Glucose Metabolism and Glucose Transporters in Breast Cancer

Shin

Koo

2021

Front. Cell Dev. Biol.

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“…PHGDH is the first enzyme of the serine biosynthesis pathway, in which it converts 3phosphoglycerate to 3-phosphonooxypyruvate. PHGDH is overexpressed and/or amplified in 70% of triple-negative breast cancers (TNBC) and some other cancers such as melanoma 23,24 and its activity is important for cancer proliferation [25][26][27][28] . However, to which extent intra-tumor heterogeneity in PHGDH protein expression exists remains elusive.…”

Section: Heterogeneous and Low Phgdh Protein Expression In Primary Tumentioning

confidence: 99%

Heterogeneity in PHGDH protein expression potentiates cancer cell dissemination and metastasis

Rossi

Doglioni

Bornes

et al. 2021

Preprint

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Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs. Genetic, transcriptional and translational intra-tumor heterogeneity contributes to this dynamic process. Beyond this, metabolic intra-tumor heterogeneity has also been observed, yet its role for cancer progression remains largely elusive. Here, we discovered that intra-tumor heterogeneity in phosphoglycerate dehydrogenase (PHGDH) protein expression drives breast cancer cell dissemination and metastasis formation. Specifically, we observed intra-tumor heterogeneous PHGDH expression in primary breast tumors, with low PHGDH expression being indicative of metastasis in patients. In mice, Phgdh protein, but not mRNA, expression is low in circulating tumor cells and early metastatic lesions, leading to increased dissemination and metastasis formation. Mechanistically, low PHGDH protein expression induces an imbalance in glycolysis that can activate sialic acid synthesis. Consequently, cancer cells undergo a partial EMT and show increased p38 as well as SRC phosphorylation, which activate cellular programs of dissemination. In turn, inhibition of sialic acid synthesis through knock-out of cytidine monophosphate N-acetylneuraminic acid synthetase (CMAS) counteracts the increased cancer cell dissemination and metastasis induced by low PHGDH expression. In conclusion, we find that heterogeneity in PHGDH protein expression promotes cancer cell dissemination and metastasis formation.

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“…In a more general scope, the use of SSRIs including sertraline (Zoloft) is associated with a reduced risk of bladder cancer [56], heptacellular carcinoma [57], ovarian cancer [58], colorectal cancer [59] and with an extended survival in several cancers [60,61]. Using animal, tissues or cellular models, numerous studies have pointed out the anti-tumoral properties of sertraline although not converging to a unified mechanism [62,63,64,65,66,67,68,69]. The anti-tumoral properties of thioridazine have also been extensively supported by several independent studies [70,71,72,73,74,75] with ligand concentration down to 10 µM.…”

Section: Discussionmentioning

confidence: 99%