CaMKII Inhibitor KN-62 Blunts Tumor Response to Hypoxia by Inhibiting HIF-1α in Hepatoma Cells

Lee, Kyoung Hwa

doi:10.4196/kjpp.2010.14.5.331

Cited by 10 publications

(11 citation statements)

References 37 publications

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“…In addition, Erler et al and Reynaud et al showed that LOX expression was increased by HIF‐1α in the intratumoral hypoxic condition, and resulted in distant metastasis or bone metastasis. In the current study, comprehensive analysis using a large HCC transcriptome matrix showed that high LOX expression correlates with the expression of HIF‐1α and the hypoxia pathway.…”

Section: Discussionmentioning

confidence: 99%

Lysyl oxidase induces epithelial‐mesenchymal transition and predicts intrahepatic metastasis of hepatocellular carcinoma

et al. 2019

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Hepatocellular carcinoma ( HCC ) has high recurrence rates even after curative hepatectomy. Drug therapy for recurrence of HCC is still limited; therefore, identifying new therapeutic targets is urgently needed. We searched for genes that would predict HCC recurrence from intrahepatic metastasis in an exhaustive DNA microarray database by searching genes associated with high early recurrence rate and having higher expression in the tumor area compared to background liver. We detected lysyl oxidase ( LOX ) and validated the clinical significance of LOX in 358 patients who underwent hepatectomy. Expression of LOX was evaluated by qRT ‐ PCR , and immunohistochemical ( IHC ) staining. High LOX expression group had a significantly higher recurrence rate than the low LOX expression group (2‐year recurrence rate was 64.0% vs 24.2%, P < .0001 for IHC ) and poorer survival rate (5‐year rate was 60.1% vs 86.2%, P < .0001 for IHC ). Multivariate analysis showed that high LOX expression was an independent risk factor for early recurrence ( IHC : HR , 2.52; P < .0001). Bioinformatic analysis showed that LOX expression was associated with hypoxia‐inducible factor‐1α ( HIF ‐1α) and the hypoxia cascade, suggesting that HIF ‐1α or hypoxia regulates LOX expression and induces epithelial‐mesenchymal transition ( EMT ). In vitro, LOX and HIF ‐1α were involved in migration and invasion capability. High LOX expression is associated with EMT markers and predicts early recurrence and poor survival in patients with HCC . These findings indicate that lysyl oxidase could be a potential therapeutic target for early recurrence of HCC .

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Section: Discussionmentioning

confidence: 99%

Lysyl oxidase induces epithelial‐mesenchymal transition and predicts intrahepatic metastasis of hepatocellular carcinoma

et al. 2019

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“…Although we were the first to report that α-CaMKII is expressed in osteosarcoma cell lines and describe the role it plays in controlling cell cycle progression (15), others have also reported that the pharmacologic inhibition of CaMKII attenuates the growth and tumorigenicity of many cancer cell lines, including LN-215, LNCaP, C4-2B, CWR22Rv1 and Hep3B (35–37). To expand on our published studies, we generated osteosarcoma cell lines where α-CaMKII is either deleted (MG-63 and 143B) or overexpressed (HOS).…”

Section: Discussionmentioning

confidence: 99%

Alpha-CaMKII Plays a Critical Role in Determining the Aggressive Behavior of Human Osteosarcoma

Daft

Yuan

Warram

et al. 2013

Molecular Cancer Research

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Osteosarcoma is among the most frequently occurring primary bone tumors, primarily affecting adolescents and young adults. Despite improvements in osteosarcoma treatment, more specific molecular targets are needed as potential therapeutic options. One target of interest is alpha-Ca2+/calmodulin-dependent protein kinase II (α-CaMKII), a ubiquitous mediator of Ca2+-linked signaling, which has been shown to regulate tumor cell proliferation and differentiation. Here, we investigate the role of α-CaMKII in the growth and tumorigenicity of human osteosarcoma. We show that α-CaMKII is highly expressed in primary osteosarcoma tissue derived from 114 patients and is expressed in varying levels in different human osteosarcoma cell lines (HOS, MG-63, MNNG/HOS and 143B). To examine whether α-CaMKII regulates osteosarcoma tumorigenic properties, we genetically inhibited α-CaMKII in two osteosarcoma cell lines using two different α-CaMKII shRNAs delivered by lentiviral vectors and overexpressed α-CaMKII by retrovirus. The genetic deletion of α-CaMKII by shRNA in MG-63 and 143B cells resulted in decreased proliferation (50 and 41%), migration (22 and 25%) and invasion (95 and 90%), respectively. The overexpression of α-CaMKII in HOS cells resulted in increased proliferation (240%), migration (640%) and invasion (10,000%). Furthermore, α-CaMKII deletion in MG-63 cells significantly reduced tumor burden in vivo (65%), while α-CaMKII overexpression resulted in tumor formation in a previously non-tumor forming osteosarcoma cell line (HOS). Our results suggest that α-CaMKII plays a critical role in determining the aggressive phenotype of osteosarcoma, and its inhibition could be an attractive therapeutic target to combat this devastating adolescent disease.

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“…Previous studies have reported that chronic ischemia has a direct association with coronary angiogenesis, but the underlying molecular mechanisms are unclear [23,24]. It has been shown that CaMKII inhibition blunted tumor response to hypoxia [17] and that CaMKII is likely the upstream signal of the hypoxia inducible factor-1 alpha (HIF-1α) in macrophage and some cancer cell lines [14][15][16]. Indeed, oxidative stress and calcium entry caused by repetitive ischemia can both activate CaMKII [25][26][27].…”

Section: Discussionmentioning

confidence: 99%

“…Growing evidence showed that CaMKII activation may have potential connection with the increased expression of VEGF [14][15][16]. It has been demonstrated that CaMKII is capable of regulating the response of tumor to hypoxia via activating VEGF promoters [17]. However, whether CaMKII can stimulate VEGF expression and coronary angiogenesis in IHD has not yet been reported.…”

Section: Introductionmentioning

confidence: 96%

Repetitive Transient Ischemia-Induced Cardiac Angiogenesis is Mediated by Camkii Activation

Chen¹,

Li²,

Dong³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Coronary angiogenesis is an important protective mechanism in response to myocardial ischemia in coronary artery disease. However, the underlying mechanisms remain largely unclear. Here, we investigated the role of CaMKII activation in ischemiainduced cardiac angiogenesis. Methods: Repetitive transient ischemia model was established in C57/BL6 mice by daily multiple episodes (3 times/day) of short time (5 min) occlusion of the left anterior descending coronary artery for 7 days. Coronary angiogenesis was detected by immunofluorescent staining. RT-qPCR and Western blot analyses were used to detect the mRNA and protein levels of CaMKII, p-CaMKII and VEGF. Primary cardiac microvascular endothelial cells (CMECs) were isolated to investigate the effects of KN93 on cell proliferation and migration in hypoxic condition. Results: We found that angiogenesis was induced in the ischemic myocardium and suppressed by chronic intraperitoneal injection of CaMKII inhibitor KN93. RT-qPCR and Western blot analyses showed that myocardial ischemia induced an increased expression and autophosphorylation of CaMKII. VEGF expression was increased in the ischemia model but blunted by KN93. Moreover, KN93 suppressed the proliferation and migration of cardiac endothelial cells in hypoxic condition in which the protein expression of CaMKII, p-CaMKII and VEGF was increased. Conclusion: CaMKII is an important mediator for the ischemia-induced coronary angiogenesis, in which CaMKII-triggered VEGF expression plays a key role.

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CaMKII Inhibitor KN-62 Blunts Tumor Response to Hypoxia by Inhibiting HIF-1α in Hepatoma Cells

Cited by 10 publications

References 37 publications

Lysyl oxidase induces epithelial‐mesenchymal transition and predicts intrahepatic metastasis of hepatocellular carcinoma

Lysyl oxidase induces epithelial‐mesenchymal transition and predicts intrahepatic metastasis of hepatocellular carcinoma

Alpha-CaMKII Plays a Critical Role in Determining the Aggressive Behavior of Human Osteosarcoma

Repetitive Transient Ischemia-Induced Cardiac Angiogenesis is Mediated by Camkii Activation

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