PI3K alpha inhibitors sensitize esophageal squamous cell carcinoma to radiation by abrogating survival signals in tumor cells and tumor microenvironment

doi:10.1016/j.canlet.2019.05.040

	PI3K alpha inhibitors sensitize esophageal squamous cell carcinoma to radiation by abrogating survival signals in tumor cells and tumor microenvironment
	Shi, Jia-jie 1,2; Xing, Hui 1,2; Wang, Yu-xiang 1,2; Zhang, Xi 1; Zhan, Qi-min 3,4; Geng, Mei-yu 2,5; Ding, Jian 2,5; Meng, Ling-hua 1,2
刊名	CANCER LETTERS
	2019
卷号	459 页码:145-155
关键词	CYH33 Radiation Synergism ESCC PI3K alpha
ISSN号	0304-3835
DOI	10.1016/j.canlet.2019.05.040
通讯作者	Ding, Jian(jding@simm.ac.cn) ; Meng, Ling-hua(lhmeng@simm.ac.cn)
英文摘要	Radiotherapy is one of the standard therapies for esophageal squamous cell carcinoma (ESCC), but the efficacy is far from desirable. Large scale genome sequencing reveals PI3K alpha is frequently hyper-activated in ESCC. We found that ESCC cells harboring alterations in PI3K pathway were more resistant to radiation and combination of a clinical PI3K alpha-selective inhibitor CYH33 and radiation synergistically inhibited cell proliferation in 14 ESCC cell lines. Radiation induced phosphorylation of FOXO1 and Akt, which sensitized ESCC cells to PI3K alpha inhibitors. Both S1PR3 and DNA-PK contributed to radiation-induced Akt phosphorylation, which were revealed to be collectively dependent on PI3K alpha. By contrast, constitutively active Akt abrogated the synergism between PI3K alpha inhibitors and radiation. PI3K alpha inhibition enhanced radiation-induced DNA damage, G2/M arrest and apoptosis. Combination of CYH33 and radiation significantly inhibited the growth of xenografts derived from ESCC patients, which was accompanied with abrogation of radiation-induced phosphorylation of Akt and filtration of M2-like macrophages. Taken together, combination of CYH33 and radiation possesses synergism in ESCC, which provides promising rationale to test this combinatorial regimen in ESCC patients.
资助项目	Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020111] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020235] ; National Science and Technology Major Project Key New Drug Creation and Manufacturing Program[2018ZX09711002-011-014] ; National Science and Technology Major Project Key New Drug Creation and Manufacturing Program[2018ZX09711002-004-011] ; National Science and Technology Major Project Key New Drug Creation and Manufacturing Program[2018ZX09711002-004-004] ; National Natural Science Foundation of China[81773760]
WOS关键词	CANCER-CELLS ; HEAD ; NECK ; PI3K ; AKT ; MACROPHAGES ; RESISTANCE ; PARP
WOS研究方向	Oncology
语种	英语
出版者	ELSEVIER IRELAND LTD
WOS记录号	WOS:000480670800014
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/288940]
专题	中国科学院上海药物研究所
通讯作者	Ding, Jian; Meng, Ling-hua
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, 501 Halite Rd, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Chinese Acad Med Sci, Canc Inst & Canc Hosp, State Key Lab Mol Oncol, Beijing 100021, Peoples R China 4.Peking Union Med Coll, Beijing 100021, Peoples R China 5.Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Shi, Jia-jie,Xing, Hui,Wang, Yu-xiang,et al. PI3K alpha inhibitors sensitize esophageal squamous cell carcinoma to radiation by abrogating survival signals in tumor cells and tumor microenvironment[J]. CANCER LETTERS,2019,459:145-155.
APA	Shi, Jia-jie.,Xing, Hui.,Wang, Yu-xiang.,Zhang, Xi.,Zhan, Qi-min.,...&Meng, Ling-hua.(2019).PI3K alpha inhibitors sensitize esophageal squamous cell carcinoma to radiation by abrogating survival signals in tumor cells and tumor microenvironment.CANCER LETTERS,459,145-155.
MLA	Shi, Jia-jie,et al."PI3K alpha inhibitors sensitize esophageal squamous cell carcinoma to radiation by abrogating survival signals in tumor cells and tumor microenvironment".CANCER LETTERS 459(2019):145-155.