p53 Promotes chemoresponsiveness by regulating hexokinase II gene transcription and metabolic reprogramming in epithelial ovarian cancer

Han, Chae Young; Patten, David A.; Lee, Seung Gee; Parks, Robin J.; Chan, David W.; Harper, Mary‐Ellen; Tsang, Benjamin K.

doi:10.1002/mc.23106

Cited by 33 publications

(27 citation statements)

References 47 publications

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“…The chemosensitizing effect of metformin seems to be correlated with p53 function. In the presence of p53 , metformin suppresses hexokinase II (glycolytic enzyme) and pyruvate dehydrogenase kinase (anti-apoptotic serine/threonine kinase) [ 72 ]. As a result, EOC cells are sensitized to metformin.…”

Section: Metformin and Ovarian Cancermentioning

confidence: 99%

Wise Management of Ovarian Cancer: On the Cutting Edge

Boussios

Mikropoulos

Samartzis

et al. 2020

JPM

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Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality among women. Two-thirds of patients present at advanced stage at diagnosis, and the estimated 5 year survival rate is 20–40%. This heterogeneous group of malignancies has distinguishable etiology and molecular biology. Initially, single-gene sequencing was performed to identify germline DNA variations associated with EOC. However, hereditary EOC syndrome can be explained by germline pathogenic variants (gPVs) in several genes. In this regard, next-generation sequencing (NGS) changed clinical diagnostic testing, allowing assessment of multiple genes simultaneously in a faster and cheaper manner than sequential single gene analysis. As we move into the era of personalized medicine, there is evidence that poly (ADP-ribose) polymerase (PARP) inhibitors exploit homologous recombination (HR) deficiency, especially in breast cancer gene 1 and 2 (BRCA1/2) mutation carriers. Furthermore, extensive preclinical data supported the development of aurora kinase (AURK) inhibitors in specific tumor types, including EOC. Their efficacy may be optimized in combination with chemotherapeutic or other molecular agents. The efficacy of metformin in ovarian cancer prevention is under investigation. Certain mutations, such as ARID1A mutations, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which are specific in ovarian clear cell carcinoma (OCCC) and endometrioid ovarian carcinoma (EnOC), may offer additional therapeutic targets in these clinical entities. Malignant ovarian germ cell tumors (MOGCTs) are rare and randomized trials are extremely challenging for the improvement of the existing management and development of novel strategies. This review attempts to offer an overview of the main aspects of ovarian cancer, catapulted from the molecular mechanisms to therapeutic considerations.

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Section: Metformin and Ovarian Cancermentioning

confidence: 99%

Wise Management of Ovarian Cancer: On the Cutting Edge

Boussios

Mikropoulos

Samartzis

et al. 2020

JPM

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“…Although the mechanism of the Warburg effect is still unclear, it is believed that the relevant mechanisms may include mitochondrial dysfunction, hypoxia, tumor gene signaling, and abnormal expression of certain metabolic enzymes. Some studies have shown that hexokinase was overexpressed in tumor cells, among which GLUT1 plays a key role in initiating and maintaining the high glucose catabolic rate required for the rapid growth of tumor cells [15] . To elucidate the role of LH‐20‐15 in glycometabolism, the expression levels of GLUT1, HK2, and LDHA were examined by using Western blot analysis.…”

Section: Resultsmentioning

confidence: 99%

Purification of Gekko Small Peptide Fraction and Its Effect of Inducing Apoptosis of EC 9706 Esophageal Cancer Cells by Inhibiting PI3K/Akt/GLUT1 Signaling Pathway

Xingzhi

et al. 2021

Chemistry & Biodiversity

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This study aimed to isolate and purify a cytotoxic extraction from Gekko japonicus, identify its components and determine its cytotoxic activity in vitro. We isolated and identified the most potent cytotoxic Gekko small peptide LH‐20‐15. The identification and analysis of peptide sequences of LH‐20‐15 were performed by de novo peptide sequencing, and two new peptides were found. LH‐20‐15 significantly inhibited the proliferation of human esophageal squamous carcinoma EC 9706 cells in a dose‐dependent manner. Furthermore, LH‐20‐15 induced apoptosis in esophageal cancer cells by activating the mitochondrial apoptotic pathway. Further research showed that LH‐20‐15 inhibited the PI3 K/Akt/GLUT1 signaling pathway. In conclusion, LH‐20‐15 from Gekko japonicus is a peptide mixture and may inhibit EC 9706 cell proliferation and induce apoptosis by activating the mitochondrial apoptotic pathway. It also regulates glucose metabolism by targeting the PI3 K/Akt/GLUT1 signaling pathway. These small peptides could be new sources of natural cytotoxic ingredients against esophageal cancer with potential drug values.

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“…TP53 is a well-known tumor suppressor that induces growth arrest or apoptosis and involved in cell cycle regulation. 28 TP53 is downregulated in many types of tumors including non-small cell lung cancer, colorectal cancer, cervical cancer and ovarian cancer, [29][30][31][32][33][34] which can lead to a poor survival rate. Our results showed that TP53 was downregulated in OC tissues, and could be decreased by miR-183-5p mimics and restored by overexpressed LEMD1-AS1, respectively.…”

Section: Discussionmentioning

confidence: 99%

<p>LEMD1-AS1 Suppresses Ovarian Cancer Progression Through Regulating miR-183-5p/TP53 Axis</p>

Guo¹,

Qin²

2020

OTT

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Background/Aims: Long noncoding RNAs (lncRNAs) play a critical role in tumorigenesis and progression of ovarian cancer (OC). This study focused on the function and potential mechanism toward LEMD1-AS1 (LEMD1 antisense RNA 1) in the progression of ovarian cancer. Materials and Methods: The expression of LEMD1-AS1 in OC tissues was evaluated in TCGA and Gene Expression Omnibus datasets (GSE119056) and confirmed in OC cell lines via qRT-PCR (quantitative real-time polymerase chain reaction). Then, the location of LEMD1-AS1 in the cytoplasmic and nuclear RNAs extracted from OV cells was detected by qRT-PCR. Cell Counting Kit-8 (CCK-8), colony formation, wound-healing and transwell assays were applied to examine cell viability, proliferation, migration and invasion, respectively. Further, the effect of LEMD1-AS1 on OC tumor growth was determined via subcutaneous xenotransplanted tumor model. The potential target for LEMD1-AS1 was validated via dual-luciferase activity assay, RNA pull-down and RNA immunoprecipitation. Results: The expression of LEMD1-AS1 was decreased in OC tissues and cell lines. Forced overexpression of LEMD1-AS1 inhibited the proliferation, migration and invasion of ovarian cancer cells and transplanted tumor growth in nude mice. We found that LEMD1-AS1 was mainly located in the cytoplasm of OC cells and contained complementary sites of miR-183-5p. Mechanistically, our results showed that LEMD1-AS1 could directly interact with miR-183-5p and tumor protein p53 (TP53). The anti-tumor role of LEMD1-AS1 on OC progression depended on miR-183-5p-mediated TP53 expression. Conclusion: LEMD1-AS1 suppresses OC progression through sponging miR-183-5p and regulation of TP53, suggesting a novel biomarker and target for OC.

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p53 Promotes chemoresponsiveness by regulating hexokinase II gene transcription and metabolic reprogramming in epithelial ovarian cancer

Cited by 33 publications

References 47 publications

Wise Management of Ovarian Cancer: On the Cutting Edge

Wise Management of Ovarian Cancer: On the Cutting Edge

Purification of Gekko Small Peptide Fraction and Its Effect of Inducing Apoptosis of EC 9706 Esophageal Cancer Cells by Inhibiting PI3K/Akt/GLUT1 Signaling Pathway

<p>LEMD1-AS1 Suppresses Ovarian Cancer Progression Through Regulating miR-183-5p/TP53 Axis</p>

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