Magmas Inhibition in Prostate Cancer: A Novel Target for Treatment-Resistant Disease

Yang, Jianhui; Das, Bhaskar; Aljitawi, Omar; Kumar, Avinash; Das, Sasmita; Veldhuizen, Peter J. Van

doi:10.3390/cancers14112732

Cited by 5 publications

(6 citation statements)

References 35 publications

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“…Evaluation was carried out on ADPGK protein expression in several prostate cell lines. Compared with the normal prostate cell line WPMY-1 [ 28 ], the expression of ADPGK was relatively higher in LNCaP and 22Rv1 cells (Fig. 2 a).…”

Section: Resultsmentioning

confidence: 95%

ADP-dependent glucokinase controls metabolic fitness in prostate cancer progression

Xu,

Li,

et al. 2023

Military Med Res

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Background Cell metabolism plays a pivotal role in tumor progression, and targeting cancer metabolism might effectively kill cancer cells. We aimed to investigate the role of hexokinases in prostate cancer (PCa) and identify a crucial target for PCa treatment. Methods The Cancer Genome Atlas (TCGA) database, online tools and clinical samples were used to assess the expression and prognostic role of ADP-dependent glucokinase (ADPGK) in PCa. The effect of ADPGK expression on PCa cell malignant phenotypes was validated in vitro and in vivo. Quantitative proteomics, metabolomics, and extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) tests were performed to evaluate the impact of ADPGK on PCa metabolism. The underlying mechanisms were explored through ADPGK overexpression and knockdown, co-immunoprecipitation (Co-IP), ECAR analysis and cell counting kit-8 (CCK-8) assays. Results ADPGK was the only glucokinase that was both upregulated and predicted worse overall survival (OS) in prostate adenocarcinoma (PRAD). Clinical sample analysis demonstrated that ADPGK was markedly upregulated in PCa tissues vs. non-PCa tissues. High ADPGK expression indicates worse survival outcomes, and ADPGK serves as an independent factor of biochemical recurrence. In vitro and in vivo experiments showed that ADPGK overexpression promoted PCa cell proliferation and migration, and ADPGK inhibition suppressed malignant phenotypes. Metabolomics, proteomics, and ECAR and OCR tests revealed that ADPGK significantly accelerated glycolysis in PCa. Mechanistically, ADPGK binds aldolase C (ALDOC) to promote glycolysis via AMP-activated protein kinase (AMPK) phosphorylation. ALDOC was positively correlated with ADPGK, and high ALDOC expression was associated with worse survival outcomes in PCa. Conclusions In summary, ADPGK is a driving factor in PCa progression, and its high expression contributes to a poor prognosis in PCa patients. ADPGK accelerates PCa glycolysis and progression by activating ALDOC-AMPK signaling, suggesting that ADPGK might be an effective target and marker for PCa treatment and prognosis evaluation.

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Section: Resultsmentioning

confidence: 95%

ADP-dependent glucokinase controls metabolic fitness in prostate cancer progression

Xu,

Li,

et al. 2023

Military Med Res

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“…The reaction was also found efficient for the synthesis of reactants bearing nitriles and carbonyl functional groups to provide compounds 2d and 2e in good yields. Due to the excellent biological activities of chlorochromenes [ 43 , 44 , 45 , 46 ] and to evaluate the effect of substituents, we drew our attention toward the synthesis of 2f and 2g . Halogen-bearing substrates are usually found interfering and intolerant of Miyaura borylation reactions.…”

Section: Resultsmentioning

confidence: 99%

“…Next, the out this dearomative borylation process was investigated with differently substituted sitions. The reaction was also found efficient for the synthesis of reactants bearing and carbonyl functional groups to provide compounds 2d and 2e in good yields the excellent biological activities of chlorochromenes [43][44][45][46] and to evaluate the substituents, we drew our attention toward the synthesis of 2f and 2g. Halogensubstrates are usually found interfering and intolerant of Miyaura borylation re However, in contrast, under these dearomative borylation conditions, these grou well tolerated to yield 2f and 2g.…”

Section: Substrate Scope Of Dearomative Borylationmentioning

confidence: 99%

“…As a part of our ongoing effort on the development of boron-based therapeutic agents [ 43 , 44 , 45 , 46 ], we envisioned that under suitable reaction conditions, copper-catalyzed conjugate addition onto coumarins/chromones could result in borylated coumarins/chromones via a dearomative mechanism and that we could introduce these compounds to our RA backbone to substitute the hydrophobic part. To explore and expand our hypothesis, we herein report a conjugate addition of diboranes onto coumarins and chromones under simple and efficient conditions.…”

Section: Introductionmentioning

confidence: 99%

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Development of a New Methodology for Dearomative Borylation of Coumarins and Chromenes and Its Applications to Synthesize Boron-Containing Retinoids

et al. 2023

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Dearomative borylation of coumarins and chromenes via conjugate addition represents a relatively unexplored and challenging task. To address this issue, herein, we report a new and general copper (I) catalyzed dearomative borylation process to synthesize boron-containing oxacycles. In this report, the borylation of coumarins, chromones, and chromenes comprising functional groups, such as esters, nitriles, carbonyls, and amides, has been achieved. In addition, the method generates different classes of potential boron-based retinoids, including the ones with oxadiazole and anthocyanin motifs. The borylated oxacycles can serve as suitable intermediates to generate a library of compounds.

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“…These agents target various mitochondrial functions such as metabolism, apoptotic pathways, and ROS homeostasis, but so far they have not shown any significant therapeutic effects [26]. BT9 is a novel small molecule that binds to MAGMAS and potentially blocks protein trafficking across the inner membrane, and it has shown inhibitory effects on proliferation and migration in glioblastoma and prostate cancer cell lines [20, 27]. In this study, we investigated BT9 efficacy in pediatric medulloblastoma.…”

Section: Discussionmentioning

confidence: 99%

Preclinical assessment of MAGMAS inhibitor as a potential therapy for pediatric medulloblastoma

Motahari,

Lepe,

Bautista

et al. 2024

Preprint

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Medulloblastoma, the most common pediatric brain malignancy, has Sonic Hedgehog (SHH) and non-SHH group3 subtypes. MAGMAS (Mitochondrial Associated Granulocyte Macrophage colony-stimulating factor Signaling molecules) encode for mitochondrial import inner membrane translocase subunit and is responsible for translocation of matrix proteins across the inner membrane. We previously reported that a small molecule MAGMAS inhibitor, BT9, decreases cell proliferation, migration, and oxidative phosphorylation in adult glioblastoma cell lines. The aim of our study was to investigate whether the chemotherapeutic effect of BT9 can be extended to pediatric medulloblastoma.MethodsMultiple in vitro assays were performed using human DAOY (SHH activated tp53 mutant) and D425 (non-SHH group 3) cells. The impact of BT9 on cellular growth, death, migration, invasion, and metabolic activity were quantified using MTT assay, TUNEL staining, scratch wound assay, Matrigel invasion chambers, and seahorse assay, respectively. Survival following 50mg/kg BT9 treatment was assessedin vivoin immunodeficient mice intracranially implanted with D425 cells.ResultsCompared to control, BT9 treatment led to a significant reduction in medulloblastoma cell growth (DAOY, 24hrs IC50: 3.6uM, 48hrs IC50: 2.3uM, 72hrs IC50: 2.1uM; D425 24hrs IC50: 3.4uM, 48hrs IC50: 2.2uM, 72hrs IC50: 2.1uM) and a significant increase in cell death (DAOY, 24hrs p=0.0004, 48hrs p<0.0001; D425, 24hrs p=0.0001, 48hrs p=0.02). In DAOY cells, 3uM BT9 delayed migration, and significantly decreased DAOY and D425 cells invasion (p < 0.0001). Ourin vivostudy, however, did not extend survival in xenograft mouse model of group3 medulloblastoma compared to vehicle-treated controls.ConclusionsOurin vitrodata showed BT9 antitumor efficacy in DAOY and D425 cell lines suggesting that BT9 may represent a promising targeted therapeutic in pediatric medulloblastoma. These data, however, need to be further validated in animal models.

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Magmas Inhibition in Prostate Cancer: A Novel Target for Treatment-Resistant Disease

Cited by 5 publications

References 35 publications

ADP-dependent glucokinase controls metabolic fitness in prostate cancer progression

ADP-dependent glucokinase controls metabolic fitness in prostate cancer progression

Development of a New Methodology for Dearomative Borylation of Coumarins and Chromenes and Its Applications to Synthesize Boron-Containing Retinoids

Preclinical assessment of MAGMAS inhibitor as a potential therapy for pediatric medulloblastoma

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