Y box binding protein 1 inhibition as a targeted therapy for ovarian cancer

Tailor, Dhanir; Resendez, Angel; Garcia-Marques, Fernando Jose; Pandrala, Mallesh; Going, Catherine C.; Bermudez, Abel; Kumar, Vineet; Rafat, Marjan; Nambiar, Dhanya K.; Honkala, Alexander; Le, Quynh‐Thu; Sledge, George W.; Graves, Edward E.; Pitteri, Sharon J.; Malhotra, Sanjay V.

doi:10.1016/j.chembiol.2021.02.014

Cited by 28 publications

(36 citation statements)

References 56 publications

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“…Cells were lysed and soluble fraction was labeled with tandem mass Tag (TMT) followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses, as previously described. 13 , 28 Soluble protein fractions compared to the 37°C vehicle or SU086-treated groups were graphed as heatmaps ( Figure 5 A). Density of protein melting temperatures, Tm, were shifted to the right in SU086 treatment reflecting higher temperatures of protein degradation ( Figure 5 B; Figure S5 A).…”

Section: Resultsmentioning

confidence: 99%

“…27 AR-negative DU145 cells were incubated with vehicle or SU086 at 2.5 mM for 1.5 h. After incubation, cells were partitioned and subjected to incubation at 37 C, 41 C, 44 C, 47 C, 50 C, 53 C, 56 C, 59 C, 63 C, or 67 C. Cells were lysed and soluble fraction was labeled with tandem mass Tag (TMT) followed by liquid chromatography-tandem mass spectrometry (LC-MS/ MS) analyses, as previously described. 13,28 Soluble protein fractions compared to the 37 C vehicle or SU086-treated groups were graphed as heatmaps (Figure 5A). Density of protein melting temperatures, Tm, were shifted to the right in SU086 treatment reflecting higher temperatures of protein degradation (Figure 5B; Figure S5A).…”

Section: Su086 Targets Heat Shock Protein 90mentioning

confidence: 99%

“…TMT labeled samples were analyzed using LC-MS/MS in triplicate, as described by our group. 13,28 The reaction mixture was stirred at room temperature for 18 h, and then diluted with water (10 mL). The mixture was extracted with ethyl acetate (2 X 25 mL).…”

Section: Cellular Thermal Shift Assaymentioning

confidence: 99%

“…Scheme-1 3,5-dimethoxy-2-((E)-3-(3-nitrophenyl)acryloyl)phenyl 3-((2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d] imidazol-4-yl)pentanamido)ethyl)disulfaneyl)propanoate As shown in scheme 1, the title compound was synthesized according to the previously reported method for similar compound 28. Under a nitrogen atmosphere, (E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(3-nitrophenyl)prop-2-en-1-one (20.0 mg, 0.061 mmol) was taken into a clean and dry two neck round bottom flask then dry DMF (5.0 mL) was added.…”

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confidence: 99%

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SU086, an inhibitor of HSP90, impairs glycolysis and represents a treatment strategy for advanced prostate cancer

Rice

Kumar

Tailor

et al. 2022

Cell Reports Medicine

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Section: Resultsmentioning

confidence: 99%

Section: Su086 Targets Heat Shock Protein 90mentioning

confidence: 99%

Section: Cellular Thermal Shift Assaymentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

SU086, an inhibitor of HSP90, impairs glycolysis and represents a treatment strategy for advanced prostate cancer

Rice

Kumar

Tailor

et al. 2022

Cell Reports Medicine

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“…Of note, a novel small molecule, SU056, was recently reported to directly bind and inhibit YBX1 [32]. SU056 demonstrated activity in ovarian cancer models in vitro and in vivo and showed favorable biochemical and pharmacologic properties.…”

Section: Discussionmentioning

confidence: 99%

YBX1 mediates translation of oncogenic transcripts to control cell competition in AML

et al. 2021

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Persistence of malignant clones is a major determinant of adverse outcome in patients with hematologic malignancies. Despite the fact that the majority of patients with acute myeloid leukemia (AML) achieve complete remission after chemotherapy, a large proportion of them relapse as a result of residual malignant cells. These persistent clones have a competitive advantage and can re-establish disease. Therefore, targeting strategies that specifically diminish cell competition of malignant cells while leaving normal cells unaffected are clearly warranted. Recently, our group identified YBX1 as a mediator of disease persistence in JAK2-mutated myeloproliferative neoplasms. The role of YBX1 in AML, however, remained so far elusive. Here, inactivation of YBX1 confirms its role as an essential driver of leukemia development and maintenance. We identify its ability to amplify the translation of oncogenic transcripts, including MYC, by recruitment to polysomal chains. Genetic inactivation of YBX1 disrupts this regulatory circuit and displaces oncogenic drivers from polysomes, with subsequent depletion of protein levels. As a consequence, leukemia cells show reduced proliferation and are out-competed in vitro and in vivo, while normal cells remain largely unaffected. Collectively, these data establish YBX1 as a specific dependency and therapeutic target in AML that is essential for oncogenic protein expression.

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YBX1 promotes stemness and cisplatin insensitivity in intrahepatic cholangiocarcinoma via the AKT/β‐catenin axis

Shi,

Hu,

Bai

et al. 2024

The Journal of Gene Medicine

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BackgroundIntrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by a poor prognosis and closely linked to tumor stemness. However, the key molecules that regulate ICC stemness remain elusive. Although Y‐box binding protein 1 (YBX1) negatively affects prognosis in various cancers by enhancing stemness and chemoresistance, its effect on stemness and cisplatin sensitivity in ICC remains unclear.MethodsThree bulk and single‐cell RNA‐seq datasets were analyzed to investigate YBX1 expression in ICC and its association with stemness. Clinical samples and colony/sphere formation assays validated the role of YBX1 in stemness and sensitivity to cisplatin. AZD5363 and KYA1979K explored the interaction of YBX1 with the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (PKB/AKT) and WNT/β‐catenin pathways.ResultsYBX1 was significantly upregulated in ICC, correlated with worse overall survival and shorter postoperative recurrence time, and was higher in chemotherapy‐non‐responsive ICC tissues. The YBX1‐high group exhibited significantly elevated stemness scores, and genes linked to YBX1 upregulation were enriched in multiple stemness‐related pathways. Moreover, YBX1 expression is significantly correlated with several stemness‐related genes (SOX9, OCT4, CD133, CD44 and EPCAM). Additionally, YBX1 overexpression significantly enhanced the colony‐ and spheroid‐forming abilities of ICC cells, accelerated tumor growth in vivo and reduced their sensitivity to cisplatin. Conversely, the downregulation of YBX1 exerted the opposite effect. The transcriptomic analysis highlighted the link between YBX1 and the PI3K/AKT and WNT/β‐catenin pathways. Further, AZD5363 and KYA1979K were used to clarify that YBX1 promoted ICC stemness through the regulation of the AKT/β‐catenin axis.ConclusionsYBX1 is upregulated in ICC and promotes stemness and cisplatin insensitivity via the AKT/β‐catenin axis. Our study describes a novel potential therapeutic target for improving ICC prognosis.

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Y box binding protein 1 inhibition as a targeted therapy for ovarian cancer

Cited by 28 publications

References 56 publications

SU086, an inhibitor of HSP90, impairs glycolysis and represents a treatment strategy for advanced prostate cancer

SU086, an inhibitor of HSP90, impairs glycolysis and represents a treatment strategy for advanced prostate cancer

YBX1 mediates translation of oncogenic transcripts to control cell competition in AML

YBX1 promotes stemness and cisplatin insensitivity in intrahepatic cholangiocarcinoma via the AKT/β‐catenin axis

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