AMPK通路调控CEMIP诱导自噬对前列腺癌细胞anoikis耐受的影响及机制

批准号:
81772751
项目类别:
面上项目
资助金额:
55.0 万元
负责人:
邢毅飞
依托单位:
学科分类:
H1808.肿瘤微环境
结题年份:
2021
批准年份:
2017
项目状态:
已结题
项目参与者:
宋亚荣、张鹏、杨立坤、孙亚冬、侯腾、肖行远、石瑛
国基评审专家1V1指导 中标率高出同行96.8%
结合最新热点,提供专业选题建议
深度指导申报书撰写,确保创新可行
指导项目中标800+,快速提高中标率
微信扫码咨询
中文摘要
内质网应激产生的自噬可能与肿瘤细胞失巢凋亡(anoikis)耐受相关,但其调控信号及机制不清。我们发现,腺苷酸活化蛋白激酶(AMPK)通路活化可调控细胞迁移诱导蛋白(CEMIP)表达而导致前列腺癌(PCa)细胞anoikis耐受。本项目拟研究PCa细胞脱离ECM后内质网应激活化AMPK诱导的自噬与anoikis耐受的关系,明确AMPK/GSK-3β/β-catenin通路上调CEMIP表达对自噬的影响,探讨CEMIP与AMPK/GSK-3β/β-catenin及非经典Wnt通路间的相互作用及反馈调节,揭示其对能量代谢及细胞存活的影响。此外,以PERK/eIF2α/ATF4为对象,探讨AMPK-CEMIP诱导自噬的上游信号;以谷氨酰胺代谢和糖酵解为切入点,揭示AMPK-CEMIP下游靶点和效应机制;并利用循环肿瘤细胞和临床病例资料信息,深入研究PCa细胞anoikis耐受和肿瘤转移的新机制。
英文摘要
Anoikis resistance is a crucial early event for cancer metastasis cascade, and acts as a feature of high aggressiveness in cancer cells. Endoplasmic reticulum stress (ERS) triggered enhancement of autophagy and consequently alternation of energy metabolism may involve in anoikis resistance, however, the regulatory pathways and detailed mechanisms that may responsible for such molecular events are not fully understood. Previously, we have found that AMP-activated protein kinase (AMPK) pathway induced anoikis resistance in prostate cancer (PCa) cells through activation of Wnt signaling and consequent over-expression of cell migration inducing protein (CEMIP). The current proposed project aims to reveal the correlation between detachment-induced autophagy and anoikis resistance in PCa cells, and to elucidate the precise effect of AMPK/GSK-3β/β-catenin pathway in boosting autophagy by regulating expression of CEMIP. Further, it goals to investigate the cross-talks of CEMIP, AMPK/GSK-3β/β-catenin and non-canonical Wnt/Ca2+ pathways, and to uncover the downstream targets of AMPK/Wnt/CEMIP that may induce autophagy, regulate metabolism, promote cell survival, and thus trigger anoikis resistance. In addition, a common ERS pathway, PERK/eIF2α/ATF4, will be adopted to determine the upstream signaling of AMPK/Wnt/CEMIP. Moreover, circulating tumor cells (CTCs) will be harvested and isolated via CellSearch and subsequent FACS sorting (or CTC-iChip) and single cell RNA-sequencing will be applied to determine the altered expression of CEMIP, autophagy- and metabolism-related genes between organ-confined tumor cells and CTCs. The clinical and pathological profiles will be collected as well to evaluate the prognostic impact of CEMIP in PCa patients. The ultimate purpose of the study is to clarify the role of ERS-induced alternations of cellular autophagy and metabolism in boosting anoikis resistance and to uncover the novel molecular mechanism underlying anoikis resistance in PCa cells.
细胞脱离胞外基质是细胞自噬的物理性诱导因素之一,后者与肿瘤细胞失巢凋亡(anoikis)耐受相关,但其调控信号及机制不清。我们发现,腺苷酸活化蛋白激酶(AMPK)通路活化可调控细胞迁移诱导蛋白(CEMIP)表达而导致前列腺癌(PCa)细胞anoikis耐受。本项目研究PCa细胞脱离ECM后内质网应激活化AMPK诱导的自噬与anoikis耐受的关系,明确AMPK/GSK-3β/β-catenin通路上调CEMIP表达对自噬的影响,探讨CEMIP与AMPK/GSK-3β/β-catenin及非经典Wnt通路间的相互作用及反馈调节,揭示其对能量代谢及细胞存活的影响。此外,ATF4促进CEMIP转录水平,CEMIP通过促进 PKCα 膜转位进而调节 Bcl-2 中的丝氨酸 70 磷酸化,随后 导致Bcl-2/Beclin1 复合物的解离二诱导自噬。通过上述成果,发现CEMIP促进前列腺癌失巢凋亡耐受的潜在机制,为转移性前列腺癌的治疗提供了新的潜在治疗靶点。
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
AMPK/GSK3β/β-catenin cascade-triggered overexpression of CEMIP promotes migration and invasion in anoikis-resistant prostate cancer cells by enhancing metabolic reprogramming
AMPK/GSK3β/β-连环蛋白级联触发的 CEMIP 过度表达通过增强代谢重编程促进失巢凋亡抵抗性前列腺癌细胞的迁移和侵袭
DOI:10.1096/fj.201701078r
发表时间:2018-07-01
期刊:FASEB JOURNAL
影响因子:4.8
作者:Zhang, Peng;Song, Yarong;Xing, Yifei
通讯作者:Xing, Yifei
KAT2A-mediated AR translocation into nucleus promotes abiraterone-resistance in castration-resistant prostate cancer.
KAT2A介导的AR易位入核促进去势抵抗性前列腺癌的阿比特龙抵抗
DOI:10.1038/s41419-021-04077-w
发表时间:2021-08-12
期刊:Cell death & disease
影响因子:9
作者:Lu D;Song Y;Yu Y;Wang D;Liu B;Chen L;Li X;Li Y;Cheng L;Lv F;Zhang P;Xing Y
通讯作者:Xing Y
ATF4/CEMIP/PKCα promotes anoikis resistance by enhancing protective autophagy in prostate cancer cells.
ATF4/CEMIP/PKCα 通过增强前列腺癌细胞的保护性自噬来促进失巢凋亡抵抗
DOI:10.1038/s41419-021-04494-x
发表时间:2022-01-10
期刊:Cell death & disease
影响因子:9
作者:Yu Y;Liu B;Li X;Lu D;Yang L;Chen L;Li Y;Cheng L;Lv F;Zhang P;Song Y;Xing Y
通讯作者:Xing Y
Activation of BDNF/TrkB pathway promotes prostate cancer progression via induction of epithelial-mesenchymal transition and anoikis resistance
BDNF/TrkB 通路的激活通过诱导上皮间质转化和失巢凋亡抵抗促进前列腺癌进展
DOI:10.1096/fj.201802159rrr
发表时间:2020-05-11
期刊:FASEB JOURNAL
影响因子:4.8
作者:Li, Tao;Yu, Ying;Xing, Yifei
通讯作者:Xing, Yifei
CEMIP/SLC1A5调控谷氨酰胺摄取对失巢前列腺癌细胞铁死亡抵抗的影响及机制
- 批准号:81974399
- 项目类别:面上项目
- 资助金额:54.0万元
- 批准年份:2019
- 负责人:邢毅飞
- 依托单位:
TrkB/BDNF通路对前列腺癌EMT、anoikis和血管生成的影响及分子机制
- 批准号:81272847
- 项目类别:面上项目
- 资助金额:60.0万元
- 批准年份:2012
- 负责人:邢毅飞
- 依托单位:
赖氨酸特异性去甲基酶1对前列腺癌雄激素非依赖性进展的影响及机制
- 批准号:30973008
- 项目类别:面上项目
- 资助金额:28.0万元
- 批准年份:2009
- 负责人:邢毅飞
- 依托单位:
组织特异性CXCR4-siRNA对前列腺癌骨转移影响的研究
- 批准号:30300348
- 项目类别:青年科学基金项目
- 资助金额:19.0万元
- 批准年份:2003
- 负责人:邢毅飞
- 依托单位:
国内基金
海外基金
