Vnn1 pantetheinase limits the Warburg effect and sarcoma growth by rescuing mitochondrial activity

Giessner, Caroline; Millet, Virginie; Mostert, Konrad J; Gensollen, Thomas; Manh, Thien‐Phong Vu; Garibal, Marc; Diémé, Binta; Attaf, Noudjoud; Chasson, Lionel; Brouilly, Nicolas; Laprie, Caroline; Lesluyes, Tom; Blay, Jean Yves; Shintu, Laetitia; Martin, Jean‐Charles; Strauss, Erick; Galland, Franck; Naquet, Philippe

doi:10.26508/lsa.201800073

Cited by 25 publications

(44 citation statements)

References 66 publications

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“…In addition, pantothenic acid appears to have profibrotic effects, being involved in the promotion of proliferation and migration of dermal fibroblasts [21,22,23]. Moreover, pantothenic acid contributes to restoring CoA levels in the mitochondria, resulting in enhanced mitochondrial activity [24].…”

Section: Function Expression and Regulation Of Vanin 1 Under Phymentioning

confidence: 99%

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Vanin 1: Its Physiological Function and Role in Diseases

Bartucci

Salvati

Olinga

et al. 2019

IJMS

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The enzyme vascular non-inflammatory molecule-1 (vanin 1) is highly expressed at gene and protein level in many organs, such as the liver, intestine, and kidney. Its major function is related to its pantetheinase activity; vanin 1 breaks down pantetheine in cysteamine and pantothenic acid, a precursor of coenzyme A. Indeed, its physiological role seems strictly related to coenzyme A metabolism, lipid metabolism, and energy production. In recent years, many studies have elucidated the role of vanin 1 under physiological conditions in relation to oxidative stress and inflammation. Vanin’s enzymatic activity was found to be of key importance in certain diseases, either for its protective effect or as a sensitizer, depending on the diseased organ. In this review, we discuss the role of vanin 1 in the liver, kidney, intestine, and lung under physiological as well as pathophysiological conditions. Thus, we provide a more complete understanding and overview of its complex function and contribution to some specific pathologies.

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Section: Function Expression and Regulation Of Vanin 1 Under Phymentioning

confidence: 99%

“…In contrast, vanin 1′s reaction products cysteamine and pantothenic acid are involved in regulating glycolysis. Cysteamine was reported to play a role in limiting glycolysis and lactate release [24], while pantothenic acid was linked to high lactate release, indicating glycolytic activity [43].…”

Section: Function Expression and Regulation Of Vanin 1 Under Phymentioning

confidence: 99%

Vanin 1: Its Physiological Function and Role in Diseases

Bartucci

Salvati

Olinga

et al. 2019

IJMS

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“…As in most cancers, the timing of occurrence of p53 mutations affects tumor progression and prognosis [8,[151][152][153]. Similarly, in mice, the combined loss of p53 [154] or CDKN2A (Ink4/ Arf ) [66] TSGs with oncogenic RAS lead to the development of undifferentiated STS. Conditional mutations in KRAS and p53 in muscle were sufficient to provoke highgrade STS with myofibroblastic differentiation [155].…”

Section: Loss Of Tumor Suppressors Affects Several Metabolic Pathwaysmentioning

confidence: 99%

“…Reciprocally, pantothenate derives from the recycling of food-derived or cellular CoA through an extracellular degradative process involving the vanin pantetheinases [191,192]. Interestingly, a high vanin1 (VNN1) level correlates with a better prognosis in STS patients [66]. Lack of Vnn1 in CDKN2A deficient mice enhanced the proportion of fibrosarcomas compared to that of other cancers.…”

Section: Metabolic Imbalances In Stsmentioning

confidence: 99%

Metabolic landscapes in sarcomas

et al. 2021

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Metabolic rewiring offers novel therapeutic opportunities in cancer. Until recently, there was scant information regarding soft tissue sarcomas, due to their heterogeneous tissue origin, histological definition and underlying genetic history. Novel large-scale genomic and metabolomics approaches are now helping stratify their physiopathology. In this review, we show how various genetic alterations skew activation pathways and orient metabolic rewiring in sarcomas. We provide an update on the contribution of newly described mechanisms of metabolic regulation. We underscore mechanisms that are relevant to sarcomagenesis or shared with other cancers. We then discuss how diverse metabolic landscapes condition the tumor microenvironment, anti-sarcoma immune responses and prognosis. Finally, we review current attempts to control sarcoma growth using metabolite-targeting drugs.

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“…In addition, several other factors suggest that it could be possible to mitigate the potential challenge of selective inhibitor development. These include the possibility of exploiting the aspects related to the bifunctional nature of the human CoASy enzyme, and the fact that humans have a second, monofunctional DPCK which remains uncharacterized (Vozza et al, 2017;Giessner et al, 2018). This DPCK could provide redundancy that may counter any potential toxic effects from the use of DPCK-targeting inhibitors.…”

Section: Assessing Dpck As a Drug Targetmentioning

confidence: 99%

Vitamin in the Crosshairs: Targeting Pantothenate and Coenzyme A Biosynthesis for New Antituberculosis Agents

Butman

Kotze

Dowd

et al. 2020

Front. Cell. Infect. Microbiol.

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Despite decades of dedicated research, there remains a dire need for new drugs against tuberculosis (TB). Current therapies are generations old and problematic. Resistance to these existing therapies results in an ever-increasing burden of patients with disease that is difficult or impossible to treat. Novel chemical entities with new mechanisms of action are therefore earnestly required. The biosynthesis of coenzyme A (CoA) has long been known to be essential in Mycobacterium tuberculosis (Mtb), the causative agent of TB. The pathway has been genetically validated by seminal studies in vitro and in vivo. In Mtb, the CoA biosynthetic pathway is comprised of nine enzymes: four to synthesize pantothenate (Pan) from l-aspartate and α-ketoisovalerate; five to synthesize CoA from Pan and pantetheine (PantSH). This review gathers literature reports on the structure/mechanism, inhibitors, and vulnerability of each enzyme in the CoA pathway. In addition to traditional inhibition of a single enzyme, the CoA pathway offers an antimetabolite strategy as a promising alternative. In this review, we provide our assessment of what appear to be the best targets, and, thus, which CoA pathway enzymes present the best opportunities for antitubercular drug discovery moving forward.

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Vnn1 pantetheinase limits the Warburg effect and sarcoma growth by rescuing mitochondrial activity

Abstract: Expression of the Vnn1 pantetheinase by sarcomas is tumor suppressive by limiting the use of aerobic glycolysis for growth and rescuing mitochondrial activity through CoA regeneration.

Cited by 25 publications

References 66 publications

Vanin 1: Its Physiological Function and Role in Diseases

Vanin 1: Its Physiological Function and Role in Diseases

Metabolic landscapes in sarcomas

Vitamin in the Crosshairs: Targeting Pantothenate and Coenzyme A Biosynthesis for New Antituberculosis Agents

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