Blockage of LMP1-modulated store-operated Ca2+ entry reduces metastatic potential in nasopharyngeal carcinoma cell

Wei, Jiazhang; Zhang, Jinyan; Si, Yongfeng; Kanada, Masamitsu; Zhang, Zhe; Terakawa, Susumu; Watanabe, Hiroshi

doi:10.1016/j.canlet.2015.02.032

Cited by 26 publications

(31 citation statements)

References 49 publications

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“…Transgenic (flk1: GFP) zebrafish embryos were generated by natural pair-wise mating, collected and maintained in 28.5°C incubator as previously described [35]. Healthy, limpid, and fluorescent embryos were picked out at 24 hours post-fertilization (hpf) and distributed into a 24-well microplate (9 embryos/well) containing Holt Buffer.…”

Section: Methodsmentioning

confidence: 99%

Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation

Zhao

et al. 2017

Oncotarget

100

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Altered cellular metabolism is now generally acknowledged as a hallmark of cancer cells, the resultant abnormal oncometabolites cause both metabolic and nonmetabolic dysregulation and potential transformation to malignancy. A subset of cancers have been found to be associated with mutations in succinate dehydrogenase genes which result in the accumulation of succinate. However, the function of succinate in tumorigenesis remains unclear. In the present study, we aim to investigate the role of oncometabolite succinate in tumor angiogenesis. Our data demonstrated the accumulation of markedly elevated succinate in gastric cancer tissues compared with that in paracancerous tissues. Moreover, succinate was able to increase the chemotactic motility, tube-like structure formation and proliferation of primary human umbilical vascular endothelial cells (pHUVECs) in vitro, as well as promoting the blood vessel formation in transgenic zebrafish. Our mechanistic studies reveal that succinate upregulates vascular endothelial growth factor (VEGF) expression by activation of signal transducer and activator of transcription 3 (STAT3) and extracellular regulated kinase (ERK)1/2 via its receptor GPR91 in a HIF-1α independent mechanism. Taken together, these data indicate an important role of the succinate-GPR91 axis in tumor angiogenesis, which may enable development of a novel therapeutic strategy that targets cancer metabolism.

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Section: Methodsmentioning

confidence: 99%

Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation

Zhao

et al. 2017

Oncotarget

100

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“…By affecting intracellular flux of the ubiquitous second messenger Ca 2+ , EBV plays a fundamental role in progression of EBV-associated tumors. In particular, LMP1 of EBV promotes NPC cell migration and angiogenesis by augmenting store-operated Ca 2+ entry (SOCE) and transient changes in intracellular Ca 2+ levels (Dellis et al, 2011; Wei et al, 2015). This enhances the activity of the Ca 2+ -dependent protease, calpain, which catalyzes cleavage of adhesion proteins, such as integrins (Potts et al, 1994; Rintanen et al, 2012), talin (Franco et al, 2004), and focal adhesion kinase (FAK) (Cortesio et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Epstein-Barr virus-encoded LMP2A stimulates migration of nasopharyngeal carcinoma cells via EGFR/Ca2+/calpain/ITGβ4 axis

et al. 2017

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Epstein-Barr virus (EBV)-encoded latent membrane protein 2A (LMP2A) promotes the motility of nasopharyngeal carcinoma (NPC) cells. Previously, we have shown that the localization of integrin β4 (ITGβ4) is regulated by LMP2A, with ITGβ4 concentrated at the cellular protrusions in LMP2A-expressing NPC cells. In the present study, we aim to further investigate mechanisms involved in this process and its contribution to cell motility. We show that expression of LMP2A was correlated with increased epidermal growth factor receptor (EGFR) activation, elevated levels of intracellular Ca2+, calpain activation and accelerated cleavage of ITGβ4. Activation of EGFR and calpain activity was responsible for a redistribution of ITGβ4 from the basal layer of NPC cells to peripheral membrane structures, which correlated with an increased migratory capacity of NPC cells. Furthermore, we demonstrated that the calpain inhibitor calpastatin was downregulated in NPC primary tumors. In conclusion, our results point to LMP2A-mediated targeting of the EGFR/Ca2+/calpain/ITGβ4 signaling system as a mechanism underlying the increased motility of NPC cells. We suggest that calpain-facilitated cleavage of ITGβ4 contributes to the malignant phenotype of NPC cells.

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“…From the opening of the Ca 2+ channel, ER stores can be refilled again . Recently, a growing body of literature has reported that SOCE is involved in the proliferation and migration of various cancers . A study of ovary carcinoma showed that SOCE participates in resistance to cisplatin .…”

Section: Introductionmentioning

confidence: 99%

“…13,14 Recently, a growing body of literature has reported that SOCE is involved in the proliferation and migration of various cancers. [15][16][17] A study of ovary carcinoma showed that SOCE participates in resistance to cisplatin. 18 However, the mechanism by which SOCE promotes the malignancy of tumor cells remains inconclusive and the role of STIM1-mediated SOCE in GIST is unclear.…”

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confidence: 99%

Inhibition of stromal‐interacting molecule 1‐mediated store‐operated Ca²⁺ entry as a novel strategy for the treatment of acquired imatinib‐resistant gastrointestinal stromal tumors

et al. 2018

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Imatinib has revolutionized the treatment of gastrointestinal stromal tumors (GIST); however, primary and secondary resistance to imatinib is still a major cause of treatment failure. Multiple mechanisms are involved in this progression. In the present study, we reported a novel mechanism for the acquired resistance to imatinib, which was induced by enhanced Ca2+ influx via stromal‐interacting molecule 1 (STIM1)‐mediated store‐operated Ca2+ entry (SOCE). We found that the STIM1 expression level was related to the acquired resistance to imatinib in our studied cohort. The function of STIM1 in imatinib‐resistant GIST cells was also confirmed both in vivo and in vitro. The results showed that STIM1 overexpression contributed to SOCE and drug response in imatinib‐sensitive GIST cells. Blockage of SOCE by STIM1 knockdown suppressed the proliferation of imatinib‐resistant GIST cell lines and xenografts. In addition, STIM1‐mediated SOCE exerted an antiapoptotic effect via the MEK/ERK pathway. The results from this study provide a basis for further research into potential novel therapeutic strategies in acquired imatinib‐resistant GIST.

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Blockage of LMP1-modulated store-operated Ca2+ entry reduces metastatic potential in nasopharyngeal carcinoma cell

Cited by 26 publications

References 49 publications

Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation

Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation

Epstein-Barr virus-encoded LMP2A stimulates migration of nasopharyngeal carcinoma cells via EGFR/Ca2+/calpain/ITGβ4 axis

Inhibition of stromal‐interacting molecule 1‐mediated store‐operated Ca²⁺ entry as a novel strategy for the treatment of acquired imatinib‐resistant gastrointestinal stromal tumors

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Blockage of LMP1-modulated store-operated Ca2+ entry reduces metastatic potential in nasopharyngeal carcinoma cell

Cited by 26 publications

References 49 publications

Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation

Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation

Epstein-Barr virus-encoded LMP2A stimulates migration of nasopharyngeal carcinoma cells via EGFR/Ca2+/calpain/ITGβ4 axis

Inhibition of stromal‐interacting molecule 1‐mediated store‐operated Ca2+ entry as a novel strategy for the treatment of acquired imatinib‐resistant gastrointestinal stromal tumors

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Inhibition of stromal‐interacting molecule 1‐mediated store‐operated Ca²⁺ entry as a novel strategy for the treatment of acquired imatinib‐resistant gastrointestinal stromal tumors