EphA2 inhibition suppresses proliferation of small-cell lung cancer cells through inducing cell cycle arrest

Ishigaki, Hirotoshi; Minami, Toshiyuki; Morimura, Osamu; Kitai, Hidemi; Horio, Daisuke; Koda, Yuichi; Fujimoto, Eriko; Negi, Yoshiki; Nakajima, Yasuhiro; Niki, Maiko; Kanemura, Shingo; Shibata, Eisuke; Mikami, Koji; Takahashi, Ryōsuke; Yokoi, Takashi; Kuribayashi, Kozo; Kijima, Takashi

doi:10.1016/j.bbrc.2019.09.076

Cited by 14 publications

(16 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Various therapeutic strategies targeting EphA2, such as EphA2 antibody, ligand Ephrin-A1, Ephrin-A1 mimic peptides, and RNA interference, have been developed 41 . It has been reported that EphA2 tyrosine kinase inhibitor, ALW-II-41-27 30 , has obvious anti-tumor effects in the many types of cancers [31][32][33][34][35][36] . As an EphA2 tyrosine kinase inhibitor, whether ALW-II-41-27 suppresses cancers by inhibiting pY772-EphA2 is unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Collectively, the results demonstrate that Shp2/Erk-1/2 signaling pathway mediates pY772-EphA2-promoting NPC cell proliferation and anchorage-independent growth. pY772-EphA2 is a target of EphA2 tyrosine kinase inhibitor ALW-II-41-27 in the NPC cells ALW-II-41-27, a novel EphA2 tyrosine kinase inhibitor 30 , has obvious anti-tumor effects in the many types of cancers [31][32][33][34][35][36] . Previous studies indicate that ALW-II-41-27 suppresses cancers by targeting S879 phosphorylation of EphA2 32,34,36 .…”

Section: Py772-epha2 Promotes Npc Cell Proliferation By Shp2/ Erk-1/2mentioning

confidence: 99%

“…An ATP-competitive EphA2 tyrosine kinase inhibitor, ALW-II-41-27 30 , possesses obvious in vitro and in vivo anti-tumor effects in lung cancer 31 – 33 , melanoma 34 , triple-negative breast cancer 35 , and intrahepatic cholangiocarcinoma 36 . As an EphA2 tyrosine kinase inhibitor, whether ALW-II-41-27 inhibits cancer progression by inhibiting pY772-EphA2 has not been explored.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Y772 phosphorylation of EphA2 is responsible for EphA2-dependent NPC nasopharyngeal carcinoma growth by Shp2/Erk-1/2 signaling pathway

Xiang

Xiao

et al. 2020

Cell Death Dis

View full text Add to dashboard Cite

EphA2 is an important oncogenic protein and emerging drug target, but the oncogenic role and mechanism of ligand-independent phosphorylation of EphA2 at tyrosine 772 (pY772-EphA2) is unclear. In this study, we established nasopharyngeal carcinoma (NPC) cell lines with stable expression of exogenous EphA2 and EphA2-Y772A (phosphorylation inactivation) using endogenous EphA2-knockdown cells, and observed that pY772A EphA2 was responsible for EphA2-promoting NPC cell proliferation and anchorage-independent and in vivo growth in mice. Mechanistically, EphA2-Y772A mediated EphA2-activating Shp2/Erk-1/2 signaling pathway in the NPC cells, and Gab1 (Grb2-associated binder 1) and Grb2 (growth factor receptor-bound protein 2) were involved in pY772-EphA2 activating this signaling pathway. Our results further showed that Shp2/Erk-1/2 signaling mediated pY772-EphA2promoting NPC cell proliferation and anchorage-independent growth. Moreover, we observed that EphA2 tyrosine kinase inhibitor ALW-II-41-27 inhibited pY772-EphA2 and EphA2-Y772A decreased the inhibitory effect of ALW-II-41-27 on NPC cell proliferation. Collectively, our results demonstrate that pY772-EphA2 is responsible for EphA2-dependent NPC cell growth in vitro and in vivo by activating Shp2/Erk-1/2 signaling pathway, and is a pharmacologic target of ALW-II-41-27, suggesting that pY772-EphA2 can serve as a therapeutic target in NPC and perhaps in other cancers.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Py772-epha2 Promotes Npc Cell Proliferation By Shp2/ Erk-1/2mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Y772 phosphorylation of EphA2 is responsible for EphA2-dependent NPC nasopharyngeal carcinoma growth by Shp2/Erk-1/2 signaling pathway

Xiang

Xiao

et al. 2020

Cell Death Dis

View full text Add to dashboard Cite

show abstract

“…Other researches have also identi ed the role of EphA2 in various tumors. For examples, EphA2 expression is elevated in small-cell lung cancer, and suppression of EphA2 has the ability to restrain cell proliferation [25]. Concerning to the regulatory role of EphA2 in cancer radioresistance, it has been described that blocking EphA2 could suppress radioresistance of NSCLC cells, as well as the migration, proliferation, and invasion of malignant cells [26].…”

Section: Discussionmentioning

confidence: 99%

Anlotinib induces tumor blood vessel normalization to strengthen the anticancer effect of radiotherapy on esophageal cancer by inhibiting EphA2

Zhu

Huang

et al. 2021

Preprint

View full text Add to dashboard Cite

Background Anlotinib has anti-tumor activity in diverse solid tumors. Given that, our study was designed to unearth the mechanism of Anlotinib in radioresistant esophageal cancer (EC) cells by modulating Ephrin type-A receptor 2 (EphA2). Methods EC cells (TE-1 and KYSE-150) were induced to radioresistant EC cells (TE-1R and KYSE-150R). EphA2 expression in TE-1R and KYSE-150R cells was measured. Then, TE-1R and KYSE-150R cells were treated with Anlotinib and/or transfected with the plasmids that altered EphA2 expression. Otherwise, TE-1R and KYSE-150R cells were transfected with si-EphA2 or OE-EphA2 plasmids independently. In vitro experiments were conducted to monitor cell proliferation, angiogenesis, migration and invasion. In vivo experiment was also implemented to observe tumor growth. Results EphA2 expression was raised in TE-1R and KYSE-150R cells. Anlotinib inhibited proliferation, angiogenesis, migration and invasion of TE-1R and KYSE-150R cells in vitro, as well as tumor growth and MVD in vivo. Inhibiting EphA2 enhanced Anlotinib-mediated effects on TE-1R and KYSE-150R cells. Down-regulating EphA2 restrained proliferation, angiogenesis, migration and invasion of TE-1R and KYSE-150R cells. Conclusion It is concluded that Anlotinib suppresses EC development under radiotherapy by inhibiting EphA2, providing another perspective to overcome radioresistance in EC.

show abstract

“…EPHA2 is a member of the ephrin receptor subfamily of protein tyrosine kinases, and EFNA1 (ephrin A1) is its ligand. Recent studies considered the EPHA2 signalling pathway as a target of cancer therapy, and revealed that blocking EPHA2 reversed the acquired resistance of gastric cancer cells to afatinib and inhibit the proliferation of small cell lung cancer cells 31,32 . In ESCC, EFNA1 and EPHA2 were upregulated, and their overexpression was correlated with short overall survival in patients 17,33,34 .…”

Section: Discussionmentioning

confidence: 99%

The miR-1224-5p/TNS4/EGFR axis inhibits tumour progression in oesophageal squamous cell carcinoma

et al. 2020

View full text Add to dashboard Cite

Oesophageal squamous cell carcinoma (ESCC) is a common and aggressive malignancy. Although many molecular alterations have been observed in ESCC, the mechanisms underlying the development and progression of this disease remain unclear. In the present study, miR-1224-5p was identified to be downregulated in ESCC tissues compared to normal tissues, and its low expression was correlated with shorter survival time in patients. In vitro experiments showed that miR-1224-5p inhibited the proliferation, colony formation, migration and invasion of ESCC cells. Mechanistic investigation revealed that miR-1224-5p directly targeted TNS4 and inhibited its expression, which led to the inactivation of EGFR-EFNA1/EPHA2-VEGFA (vascular endothelial growth factor A) signalling. Experiments in vivo confirmed the suppressive effect of miR-1224-5p on oesophageal cancer cells. By immunohistochemistry analysis of ESCC specimens, we found that TNS4 expression was positively correlated with that of VEGFA, and was significantly associated with lymph node metastasis and shorter survival time in patients. Together, our data suggest that miR-1224-5p downregulation is a frequent alteration in ESCC that promotes cell proliferation, migration, invasion and tumour growth by activating the EGFR-EFNA1/EPHA2-VEGFA signalling pathway via inhibition of TNS4 expression. Decreased miR-1224-5p and elevated TNS4 are unfavourable prognostic factors for ESCC patients.

show abstract

EphA2 inhibition suppresses proliferation of small-cell lung cancer cells through inducing cell cycle arrest

Cited by 14 publications

References 20 publications

Y772 phosphorylation of EphA2 is responsible for EphA2-dependent NPC nasopharyngeal carcinoma growth by Shp2/Erk-1/2 signaling pathway

Y772 phosphorylation of EphA2 is responsible for EphA2-dependent NPC nasopharyngeal carcinoma growth by Shp2/Erk-1/2 signaling pathway

Anlotinib induces tumor blood vessel normalization to strengthen the anticancer effect of radiotherapy on esophageal cancer by inhibiting EphA2

The miR-1224-5p/TNS4/EGFR axis inhibits tumour progression in oesophageal squamous cell carcinoma

Contact Info

Product

Resources

About