Heat Shock Protein 27, a Novel Downstream Target of Collagen Type XI alpha 1, Synergizes with Fatty Acid Oxidation to Confer Cisplatin Resistance in Ovarian Cancer Cells

Heiserman, James Patrick; Nallanthighal, Sameera; Gifford, Cody C.; Graham, Kayla; Samarakoon, Rohan; Gao, Chao; Sage, Jessica; Zhang, Wenzheng; Higgins, Paul J.; Cheon, Dong‐Joo

doi:10.3390/cancers13194855

Cited by 12 publications

(26 citation statements)

References 47 publications

(94 reference statements)

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“…An enrichment of acetylated histones H3 was found around the BIRC3 promoter (Figure 5B), which suggests that NF-κB-enhanced expression of BIRC3 may occur by promoting histone acetylation in ESCA, just like that in breast cancer [28]. Activated NF-κB and up-regulated IAPs (BIRC2 and BIRC3) in ovarian cancer cells might mediate chemotherapy resistance [29].…”

Section: Discussionmentioning

confidence: 92%

Expression Analysis of BIRC3 as One Target Gene of Transcription Factor NF-κB for Esophageal Cancer

Luo

Zhu

et al. 2022

Processes

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Esophageal cancer (ESCA) is one of the highest lethal malignancy tumors worldwide. Baculoviral IAP repeat-containing protein 3 (BIRC3) is the main inhibitor of apoptosis in many malignancies. The aim of this study was to clarify how BIRC3 acts in ESCA cells. Through TNMplot and GEPIA2 analysis, BIRC3 was found abundantly expressed in ESCA cells. The quantitative RT-PCR assay confirmed BIRC3 was pronouncedly induced in all used ESCA cell lines. In addition, proinflammatory cytokines TNFα and IL-1β were shown to have promotion effects on BIRC3 expression in ESCA cells. These promotive effects were blocked when the function of NF-κB was inhibited by bay 11-7082, which indicates the expression of the BIRC3 gene was regulated via the NF-κB transcription pathway in ESCA. Moreover, bioinformatics analysis showed that the BIRC3 gene had many NF-κB binding cis-elements. Chromatin immunoprecipitation was then performed and it was found that NF-κB directly interacts with cis-elements of the BIRC3 gene. In conclusion, our data proved that the high expression level of BIRC3 maintained the survival of ESCA cells. BIRC3 was up-regulated by proinflammatory cytokine TNFα and IL-1β through the NF-κB signaling pathway, and this may be helpful for esophageal cancer prevention and therapy.

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Section: Discussionmentioning

confidence: 92%

Expression Analysis of BIRC3 as One Target Gene of Transcription Factor NF-κB for Esophageal Cancer

Luo

Zhu

et al. 2022

Processes

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“…Acylcarnitines are generated via esterification of fatty acids and shuttle lipids into the mitochondrial matrix for β-oxidation ( 39 ). Reduced acylcarnitine levels imply impaired fatty acid oxidation and mitochondrial dysfunction, which are implicated in OC ( 40 , 41 ). Additionally, an association was observed between tetradecanoylcarnitine and a diminished risk of HGSOC.…”

Section: Discussionmentioning

confidence: 99%

Mendelian randomization analysis to elucidate the causal relationship between small molecule metabolites and ovarian cancer risk

Chang,

Liu,

Han

2023

Front. Oncol.

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BackgroundSmall molecule metabolites are potential biomarkers for ovarian cancer. However, the causal relationship between small molecule metabolites and ovarian cancer remains unclear.MethodsSingle nucleotide polymorphisms (SNPs) correlated with 53 distinct small molecule metabolites were identified as instrumental variables (IVs) from comprehensive genome-wide association studies. Aggregate data encompassing 25,509 cases of ovarian cancer and 40,941 controls of European descent were procured from the Ovarian Cancer Association Consortium. To evaluate causative associations, four Mendelian randomization techniques—including inverse-variance weighted, weighted median, maximum likelihood, and MR-Egger regression—were employed.ResultsIn total, 242 SNPs were delineated as IVs for the small molecule metabolites under consideration. A significant association with the overarching risk of ovarian cancer was observed for six distinct metabolites. Hexadecenoylcarnitine and methioninesulfoxide were associated with a 32% and 31% reduced risk, respectively. Fifteen metabolites were linked to subtype ovarian cancers. For instance, both methionine sulfoxide and tetradecanoyl carnitine exhibited an inverse association with the risk of clear cell and high-grade serous ovarian cancers. Conversely, tryptophan demonstrated a 1.72-fold elevated risk for endometrioid ovarian cancer.ConclusionThis study identified several metabolites with putative causal effects on ovarian cancer risk using Mendelian randomization analysis. The findings provide insight into the etiological role of small molecule metabolites and highlight potential early detection biomarkers for ovarian cancer. Subsequent investigations are imperative to corroborate these findings and elucidate the underlying pathophysiological mechanisms.

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“…Increasing reports demonstrated that FAO contributed to chemoresistance in gastric [ 28 ], breast [ 29 ], ovarian [ 30 ], and hepatocellular carcinomas [ 31 ]. Pharmacological inhibition of FAO sensitized leukemia cells to apoptosis [ 32 ], and synergetic of FAO inhibitors with Ara-C eradicated bone marrow resident chemoresistance AML cells [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of SIRT3 SUMOylation Confers AML Chemoresistance via Controlling HES1-Dependent Fatty Acid Oxidation

Zhang

Shen

Wei

et al. 2022

IJMS

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Sirtuin 3 (SIRT3) deacetylase is a key regulator for chemoresistance in acute myeloid leukemia (AML) cells due to its capability of modulating mitochondrial metabolism and reactive oxygen species (ROS). SIRT3 is de-SUMOylated by SUMO-specific peptidase 1 (SENP1), which enhances its deacetylase activity. Therefore, dysregulation of SIRT3 SUMOylation may lead to fortified chemoresistance in AML. Indeed, SIRT3 de-SUMOylation was induced by chemotherapeutic agents, which in turn, exacerbated resistance against chemotherapies in AML by activating SIRT3 via preventing its proteasome degradation. Furthermore, RNA-seq revealed that expression of a collection of genes was altered by SIRT3 de-SUMOylation including inhibition of transcription factor Hes Family BHLH Transcription Factor 1 (HES1), a downstream substrate of Notch1 signaling pathway, leading to increased fatty acids oxidation (FAO). Moreover, the SENP1 inhibitor momordin-Ic or HES1 overexpression synergized with cytarabine to eradicate AML cells in vitro and in xenograft mouse models. In summary, the current study revealed a novel role of SIRT3 SUMOylation in the regulation of chemoresistance in AML via HES1-dependent FAO and provided a rationale for SIRT3 SUMOylation and FAO targeted interventions to improve chemotherapies in AML.

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Heat Shock Protein 27, a Novel Downstream Target of Collagen Type XI alpha 1, Synergizes with Fatty Acid Oxidation to Confer Cisplatin Resistance in Ovarian Cancer Cells

Cited by 12 publications

References 47 publications

Expression Analysis of BIRC3 as One Target Gene of Transcription Factor NF-κB for Esophageal Cancer

Expression Analysis of BIRC3 as One Target Gene of Transcription Factor NF-κB for Esophageal Cancer

Mendelian randomization analysis to elucidate the causal relationship between small molecule metabolites and ovarian cancer risk

Dysregulation of SIRT3 SUMOylation Confers AML Chemoresistance via Controlling HES1-Dependent Fatty Acid Oxidation

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