Abstract 4511: HIF-1-dependent regulation of creatine kinase metabolism promotes breast cancer invasion and metastasis

磷酸肌酸 转移 癌症研究 转移性乳腺癌 肌酸 生物 基因敲除 激酶 癌细胞 乳腺癌 乳腺肿瘤 癌症 内科学 内分泌学 医学 细胞培养 细胞生物学 遗传学 能量代谢
作者
Hilaire C. Barch,Danielle L. Brooks,Raisa I. Krutilina,Luciana P. Schwab,Deanna N. Parke,Tiffany N. Seagroves
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:77 (13_Supplement): 4511-4511 被引量:1
标识
DOI:10.1158/1538-7445.am2017-4511
摘要

Abstract Dysregulated tumor cell metabolism is a hallmark of cancer progression and therapeutic resistance. In a screen for Hypoxia-Inducible Factor (HIF)-dependent genes regulating metabolism, we identified creatine kinase, brain isoform (CKB) as down-regulated in HIF-1 knockout mammary tumor cells. Creatine kinases (CKs) reversibly catalyze the transfer of a high-energy phosphoryl group from ATP to creatine, generating phosphocreatine in the forward reaction, and ATP in the reverse reaction. CKs are up-regulated in a variety of solid tumors, including ovarian, breast, colon, lung and brain. Knockdown of CKB in the polyoma middle T (PyMT) transgenic mouse model of metastatic breast cancer suppressed the production of intracellular ATP and invasion in vitro, and inhibited metastasis from the mammary gland to the lung in vivo. CK activity is known to be inhibited by cyclocreatine, a creatine kinase substrate that represses CK-dependent generation of ATP from phosphocreatine. When female FVB/Nj mice were injected with wild type PyMT cells in a tail vein assay and then treated with cCr (1g/kg/day, IP), lung metastasis was repressed to the same extent as Ckb gene knockdown. Moreover, when cCr therapy was administered 7 days after tail vein injection, cCr was effective in preventing the transition of lung micrometastases to macrometastases. To explore the role of CK activity in regulating cell proliferation, survival in suspension, cellular metabolism and invasion, we next created CKB loss- and gain-of-function models using human breast cancer cell lines, and compared phenotypes to cCr treatment. Whereas deletion of CKB had no effect on cell proliferation or survival in adherent conditions or in suspension, either deletion of CKB or cCr therapy potently reduced ATP levels and invasive potential in vitro. Preliminary data also indicate that pre-treatment of triple negative breast cancer cell lines with cCr sensitizes cells to doxorubicin. Together, these data suggest that inhibition of CK activity may be effective in treating stage IV breast cancer. We are currently testing whether cCr has anti-metastatic efficacy as a monotherapy, or in combination with conventional chemotherapies, using luciferase-labeled patient-derived xenograft (PDX) models. This work was sponsored by the NIH (CA138488), the Dept. of Defense (BC150640), the METAvivor foundation, and the West Cancer Center in Memphis, TN. Citation Format: Hilaire Barch, Danielle L. Brooks, Raya Krutilina, Luciana P. Schwab, Deanna Parke, Tiffany N. Seagroves. HIF-1-dependent regulation of creatine kinase metabolism promotes breast cancer invasion and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4511. doi:10.1158/1538-7445.AM2017-4511

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
伶俐白凝完成签到 ,获得积分10
2秒前
doclarrin完成签到 ,获得积分10
4秒前
jewel9完成签到,获得积分10
15秒前
迷人面包完成签到,获得积分0
17秒前
e746700020完成签到,获得积分10
26秒前
复杂觅山完成签到 ,获得积分10
30秒前
Tong完成签到,获得积分0
32秒前
CLTTT完成签到,获得积分10
33秒前
hua完成签到 ,获得积分10
40秒前
wang完成签到,获得积分10
43秒前
yaoyh_gc完成签到,获得积分10
46秒前
俊逸的白梦完成签到 ,获得积分10
48秒前
48秒前
Hank完成签到 ,获得积分10
57秒前
多边形完成签到 ,获得积分10
1分钟前
娇娇大王完成签到,获得积分10
1分钟前
南风完成签到 ,获得积分10
1分钟前
spy完成签到 ,获得积分10
1分钟前
1分钟前
心跳完成签到 ,获得积分10
1分钟前
娃哈哈完成签到 ,获得积分10
1分钟前
好好好完成签到 ,获得积分10
1分钟前
蛋妮完成签到 ,获得积分10
1分钟前
little2000完成签到 ,获得积分10
1分钟前
hy完成签到,获得积分10
1分钟前
1分钟前
机智的从霜完成签到 ,获得积分10
1分钟前
高高的丹雪完成签到 ,获得积分10
1分钟前
wjf123完成签到 ,获得积分10
1分钟前
开心夏旋完成签到 ,获得积分10
1分钟前
打打应助不吃别夹采纳,获得10
2分钟前
我和你完成签到 ,获得积分10
2分钟前
2分钟前
木南大宝完成签到 ,获得积分10
2分钟前
美好乐松完成签到,获得积分10
2分钟前
shidandan完成签到 ,获得积分10
2分钟前
阳光的凝冬完成签到 ,获得积分10
2分钟前
Herbs完成签到 ,获得积分10
2分钟前
落寞醉易完成签到 ,获得积分10
2分钟前
ewind完成签到 ,获得积分10
2分钟前
高分求助中
Sustainability in Tides Chemistry 2000
Microlepidoptera Palaearctica, Volumes 1 and 3 - 13 (12-Volume Set) [German] 1122
Дружба 友好报 (1957-1958) 1000
The Data Economy: Tools and Applications 1000
Mantiden - Faszinierende Lauerjäger – Buch gebraucht kaufen 700
PraxisRatgeber Mantiden., faszinierende Lauerjäger. – Buch gebraucht kaufe 700
A Dissection Guide & Atlas to the Rabbit 600
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3099800
求助须知:如何正确求助?哪些是违规求助? 2751277
关于积分的说明 7612198
捐赠科研通 2403062
什么是DOI,文献DOI怎么找? 1275162
科研通“疑难数据库(出版商)”最低求助积分说明 616276
版权声明 599053