Activation of the SphK1/ERK/p‑ERK pathway promotes autophagy in colon cancer cells

Xu, Chunyan; Zhang, Wenlu; Liu, Shiquan; Wu, Wenhong; Qin, Mengbin; Huang, Jiean

doi:10.3892/ol.2018.8588

Cited by 24 publications

(28 citation statements)

References 33 publications

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“…As it has been reported that iron chelation and ERK1/2 activation can both regulate the autophagy machinery [15,16,29,30], we wonder if autophagy is involved in this pathway. HA cells were treated with either C7, deferoxamine, Dp44mT, or their iron-precomplexed counterparts.…”

Section: Resultsmentioning

confidence: 99%

Intracellular Iron Chelation by a Novel Compound, C7, Reactivates Epstein–Barr Virus (EBV) Lytic Cycle via the ERK-Autophagy Axis in EBV-Positive Epithelial Cancers

Yiu

Hui

Choi

et al. 2018

Cancers

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Pharmaceutical reactivation of lytic cycle of Epstein–Barr virus (EBV) represents a potential therapeutic strategy against EBV-associated epithelial malignancies, e.g., gastric carcinoma (GC) and nasopharyngeal carcinoma (NPC). A novel lytic-inducing compound, C7, which exhibits structural similarity to Di-2-Pyridyl Ketone 4, 4-Dimethyl-3-Thiosemicarbazone (Dp44mT), a known chelator of intracellular iron, is found to reactivate EBV lytic cycle in GC and NPC. This study aims to investigate the role of intracellular iron chelation by C7 and other iron chelators in lytic reactivation of EBV in GC and NPC. Testing of six structural analogs of C7 revealed only those which have high affinity towards transition metals could induce EBV lytic cycle. Precomplexing C7 and iron chelators to iron prior to treatment of the cells abolished EBV lytic reactivation. Though hypoxia signaling pathway was activated, it was not the only pathway associated with EBV reactivation. Specifically, C7 and iron chelators initiated autophagy by activating extracellular signal-regulated kinase (ERK1/2) to reactivate EBV lytic cycle since autophagy and EBV lytic reactivation were abolished in cells treated with ERK1/2 blockers whilst inhibition of autophagy by 3-Methyladenine (3-MA) and atg5 knockdown significantly abolished EBV lytic reactivation. In summary, we discovered a novel mechanism of reactivation of the EBV lytic cycle through intracellular iron chelation and induction of ERK-autophagy axis in EBV-positive epithelial malignancies, raising the question whether clinically available iron chelators can be incorporated into existing therapeutic regimens to treat these cancers.

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Section: Resultsmentioning

confidence: 99%

Intracellular Iron Chelation by a Novel Compound, C7, Reactivates Epstein–Barr Virus (EBV) Lytic Cycle via the ERK-Autophagy Axis in EBV-Positive Epithelial Cancers

Yiu

Hui

Choi

et al. 2018

Cancers

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“…He et al ( 1 ) summarized the molecular mechanisms of chemoresistance in OS; however, the detailed molecular mechanisms by which SphK1 mediates doxorubicin resistance are unknown. Previous studies ( 27 , 29 , 30 ) reported that activation of the SphK1/ERK/p-ERK signaling pathway in colon cancer cells promoted autophagy, which is one of a number of mechanisms that have been reported to be responsible for chemoresistance.…”

Section: Discussionmentioning

confidence: 96%

“…In 2006, Bonhoure et al ( 25 ) reported that SphK1 contributes to MDR-associated chemoresistance in acute myeloid leukemia. The role of SphK1 in chemoresistance has also been investigated in several different types of cancer, including breast ( 26 ), colon ( 27 ) and gastroesophageal cancer ( 28 ), as well as hepatocellular carcinoma ( 12 ). A study conducted by Wang and Wu ( 12 ) reported that SphK1 expression was associated with poor prognosis and oxaliplatin resistance in hepatocellular carcinoma ( 12 ).…”

Section: Discussionmentioning

confidence: 99%

Sphingosine kinase 1 contributes to doxorubicin resistance and glycolysis in osteosarcoma

Ren

2020

Mol Med Rep

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Osteosarcoma (OS) is one of the most common and aggressive malignancies in children and adolescents worldwide. Sphingosine kinase 1 (SphK1) has recently been reported to serve a role in OS progression. The present study aimed to investigate the role of SphK1 in the development of chemoresistance and glycolysis in OS cell lines. SphK1 expression levels in OS cell lines (U2OS, MG63 and SaoS2) were analyzed using western blotting and reverse transcription-quantitative PCR (RT-qPCR). A cell survival assay was conducted to determine doxorubicin-resistance in OS cells, and glycolysis was also evaluated. SphK1 expression was increased in the U2OS and SaoS2 cell lines, and both cell lines were more resistant to doxorubicin when compared with the MG63 cell line. SphK1 knockdown or overexpression altered doxorubicin resistance and the viability of OS cell lines. In addition, hypoxia inducible factor-1α (HIF-1α) expression was positively associated with SphK1 expression, and partly mediated SphK1-induced effects on doxorubicin resistance and glycolysis. The present study suggested that SphK1 participated in the development of doxorubicin resistance and contributed to glycolysis in OS cells by regulating HIF-1α expression. However, further studies investigating the application of SphK1 associated therapies for patients with OS are required.

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“…Wang and co-workers demonstrated that microRNA-506-3p was able to inhibit autophagy through targeting Sphk1 in osteosarcoma cells [22]. In another study, authors demonstrated that Sphk1/ERK/p-ERK pathway involved in the induction of autophagy in colon cancer cells [23]. Inconsistently, it was reported that the inhibition of Sphk1 expression could induce autophagy in head and neck squamous cell carcinoma cells [24].…”

Section: Sphk1 Gene Plays An Important Role In a Variety Of Diseases mentioning

confidence: 98%

Sphk1 involves in the regulation of autophagy process in cardiac myocyte cells at high glucose condition

Xie

et al. 2019

Preprint

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Diabetic cardiomyopathy is the myocardium disorders caused by diabetes mellitus, which has become a key concern bringing heavy burden to the public health. Autophagy is one of activities involving in the pathogenesis of diabetic cardiomyopathy. Sphk1 gene plays a crucial role in cell survival and growth, and regulation of many diseases including diabetes and cardiovascular disease. However, the pathogenesis of diabetic cardiomyopathy remains poorly understood. To this aim, the study established adenovirus vectors expressing Sphk1 and shSphk1 to investigate the effects of Sphk1 on autophagy and cell survival in myocardial cells under high glucose conditions (25 mM). It was found that overexpression of Sphk1 promoted autophagy activity in H9c2 cells under high glucose treatment measured by various methodologies including qRT-PCR, western blot, fluorescence microscope, and so on. Inhibition of autophagy decreased cell vitality under high glucose condition. A broadly used medicine silibinin was demonstrated to induce autophagy in a dose-dependent manner. Herein, the findings in the present study may provide useful reference for unveiling the pathogenesis of diabetic cardiomyopathy and developing novel therapies treating diabetic cardiomyopathy.

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Activation of the SphK1/ERK/p‑ERK pathway promotes autophagy in colon cancer cells

Cited by 24 publications

References 33 publications

Intracellular Iron Chelation by a Novel Compound, C7, Reactivates Epstein–Barr Virus (EBV) Lytic Cycle via the ERK-Autophagy Axis in EBV-Positive Epithelial Cancers

Intracellular Iron Chelation by a Novel Compound, C7, Reactivates Epstein–Barr Virus (EBV) Lytic Cycle via the ERK-Autophagy Axis in EBV-Positive Epithelial Cancers

Sphingosine kinase 1 contributes to doxorubicin resistance and glycolysis in osteosarcoma

Sphk1 involves in the regulation of autophagy process in cardiac myocyte cells at high glucose condition

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