Hexokinase 2 in Cancer: A Prima Donna Playing Multiple Characters

Ciscato, Francesco; Ferrone, Lavinia; Masgras, Ionica; Laquatra, Claudio; Rasola, Andrea

doi:10.3390/ijms22094716

Cited by 137 publications

(127 citation statements)

References 108 publications

(170 reference statements)

Supporting

Mentioning

103

Contrasting

Order By: Relevance

“…HK: Hexokinase, an exose-phosphorylating enzyme for aerobic glycolysis, is overexpressed in many tumor cells ( Ciscato et al 2021 ). Treatments with 2-deoxy- d -glucose, 3-bromopyruvate, or lonidamine inhibit the key enzyme hexokinase of glycolysis, and genetic ablation of hexokinase 2 inhibits tumor growth in mouse models ( Ciscato et al 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Nonhormonal therapy for endometriosis based on energy metabolism regulation

Kobayashi

Shinmoto

Imanaka

2021

Reproduction and Fertility

View full text Add to dashboard Cite

Objectives: Ovarian function suppression is the current pharmacotherapy of endometriosis with limited benefit and adverse effects. New therapeutic strategies other than hormonal therapy are developed based on the molecular mechanisms involved in the hypoxic and oxidative stress environments and metabolism unique to endometriosis. Methods: A literature search was performed between January 2000 and March 2021 in the PubMed database using a combination of specific terms. Results: Endometriosis-associated metabolic changes have been organized into four hallmarks: (1) glucose uptake, (2) aerobic glycolysis, (3) lactate production and accumulation, and (4) metabolic conversion from mitochondrial oxidative phosphorylation (OXPHOS) to aerobic glycolysis. Endometriotic cells favor glycolytic metabolism over mitochondrial OXPHOS to produce essential energy for cell survival. Hypoxia, a common feature of the endometriosis environment, is a key player in this metabolic conversion, which may lead to glucose transporter overexpression, pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase kinase A (LDHA) activation, and pyruvate dehydrogenase complex inactivation. Evading mitochondrial OXPHOS mitigates excessive generation of reactive oxygen species (ROS) that may trigger cell death. Therefore, the coinactivation of LDHA and PDK1 can induce the accumulation of mitochondrial ROS by converting energy metabolism to mitochondrial OXPHOS, causing endometriotic cell death. Conclusion: Metabolic pattern reconstruction in endometriotic lesions is a critical factor in cell survival and disease progression. One therapeutic strategy that may avoid hormone manipulation is focused on mitigating metabolic changes that have been detected in cells/tissues from women with endometriosis.

show abstract

Section: Resultsmentioning

confidence: 99%

Nonhormonal therapy for endometriosis based on energy metabolism regulation

Kobayashi

Shinmoto

Imanaka

2021

Reproduction and Fertility

View full text Add to dashboard Cite

show abstract

“…HK2 is known to be overexpressed in various cancers and involved in maintenance of tumor malignancies. 26 Overexpression of HK2 in 5-Fu-resistant colon cancer cells provided cancer cells with growth advantages via elevated glycolysis. Here, we identified that HK2 was a direct target of miR-330-3p in CRC cells.…”

Section: Discussionmentioning

confidence: 99%

Targeting EGFR sensitizes 5-Fu-resistant colon cancer cells through modification of the lncRNA-FGD5-AS1-miR-330-3p-Hexokinase 2 axis

Gao

Ren

Liu

et al. 2021

Molecular Therapy - Oncolytics

View full text Add to dashboard Cite

5-Fluorouracil (5-Fu) is a widely applied anti-cancer agent against colorectal cancer (CRC), yet a number of CRC patients have developed resistance to 5-Fu-based chemotherapy. The epidermal growth factor receptor (EGFR) is recognized as an oncogene that promotes diverse cancer progresses. In addition, long noncoding RNAs (lncRNAs) are essential regulators of cancers. Here we report that EGFR and lncRNA-FGD5-AS1 promoted 5-Fu resistance of CRC. By establishing the 5-Fu-resistant CRC cell line, we detected that EGFR, FGD5-AS1, and glucose metabolism were significantly elevated in 5-Fu-resistant CRC cells. A microRNA-microarray analysis revealed that miR-330-3p functions as a downstream effector of FGD5-AS1. FGD5-AS1 directly sponged miR-330-3p to form a competing endogenous RNA (ceRNA) network, leading to inhibition of miR-330-3p expression. Furthermore, bioinformatics analysis revealed that Hexokinase 2 (HK2) was a potential target of miR-330-3p, which was validated by luciferase assay. Rescue experiments demonstrated that FGD5-AS1 promotes glycolysis through modulating the miR-330-3p-HK2 axis, leading to 5-Fu resistance of CRC cancer cells. Finally, in vitro and in vivo xenograft experiments consistently demonstrated that inhibition of EGFR by the specific inhibitor erlotinib effectively enhanced the anti-tumor toxicity of 5-Fu by targeting the EGFR-FGD5-AS1-miR-330-3p-HK2 pathway. In summary, this study demonstrates new mechanisms of the EGFR-modulated 5-Fu resistance through modulating the noncoding RNA network, contributing to development of new approaches against chemoresistant CRC.

show abstract

“…Collectively, we propose a complex regulatory relationship between these miRNAs and HK2 in CC. Of note, HK2 levels are regulated at the transcriptional, post-translational, and translational levels ( 31 ). Different genetic and epigenetic mechanisms may be involved in the regulation of HK2 in CC, the exact mechanisms for the upregulation of HK2 are deserving of future studies.…”

Section: Discussionmentioning

confidence: 99%

HK2 Is a Crucial Downstream Regulator of miR-148a for the Maintenance of Sphere-Forming Property and Cisplatin Resistance in Cervical Cancer Cells

et al. 2021

View full text Add to dashboard Cite

The acquisition of cancer stem-like properties is believed to be responsible for cancer metastasis and therapeutic resistance in cervical cancer (CC). CC tissues display a high expression level of hexokinase 2 (HK2), which is critical for the proliferation and migration of CC cells. However, little is known about the functional role of HK2 in the maintenance of cancer stem cell-like ability and cisplatin resistance of CC cells. Here, we showed that the expression of HK2 is significantly elevated in CC tissues, and high HK2 expression correlates with poor prognosis. HK2 overexpression (or knockdown) can promote (or inhibit) the sphere-forming ability and cisplatin resistance in CC cells. In addition, HK2-overexpressing CC cells show enhanced expression of cancer stem cell-associated genes (including SOX2 and OCT4) and drug resistance-related gene MDR1. The expression of HK2 is mediated by miR-145, miR-148a, and miR-497 in CC cells. Overexpression of miR-148a is sufficient to reduce sphere formation and cisplatin resistance in CC cells. Our results elucidate a novel mechanism through which miR-148a regulates CC stem cell-like properties and chemoresistance by interfering with the oncogene HK2, providing the first evidence that dysregulation of the miR-148a/HK2 signaling plays a critical role in the maintenance of sphere formation and cisplatin resistance of CC cells. Our findings may guide future studies on therapeutic strategies that reverse cisplatin resistance by targeting this pathway.

show abstract

Hexokinase 2 in Cancer: A Prima Donna Playing Multiple Characters

Cited by 137 publications

References 108 publications

Nonhormonal therapy for endometriosis based on energy metabolism regulation

Nonhormonal therapy for endometriosis based on energy metabolism regulation

Targeting EGFR sensitizes 5-Fu-resistant colon cancer cells through modification of the lncRNA-FGD5-AS1-miR-330-3p-Hexokinase 2 axis

HK2 Is a Crucial Downstream Regulator of miR-148a for the Maintenance of Sphere-Forming Property and Cisplatin Resistance in Cervical Cancer Cells

Contact Info

Product

Resources

About