Acid-Induced Downregulation of ASS1 Contributes to the Maintenance of Intracellular pH in Cancer

被引：44

作者：

Silberman, Alon ^{[1
]}

Goldman, Omer ^{[1
]}

Assayag, Odeya Boukobza ^{[1
]}

Jacob, Adi ^{[2
]}

Rabinovich, Shiran ^{[1
]}

Adler, Lital ^{[1
]}

Lee, Joo Sang ^{[3
,4
,5
]}

Keshet, Rom ^{[1
]}

Sarver, Alona ^{[1
]}

Frug, Julia ^{[1
]}

Stettner, Noa ^{[1
,6
]}

Galai, Sivan ^{[1
]}

Persi, Erez ^{[7
]}

Halpern, Keren Bahar ^{[2
]}

Zaltsman-Amir, Yehudit ^{[1
]}

Pode-Shakked, Ben ^{[8
,9
]}

Eilam, Raya ^{[6
]}

Anikster, Yair ^{[8
,9
]}

Nagamani, Sandesh C. S. ^{[10
]}

Ulitsky, Igor ^{[1
]}

Ruppin, Eytan ^{[3
,4
,5
]}

Erez, Ayelet ^{[1
]}

机构：

[1] Weizmann Inst Sci, Dept Regulat Biol, Rehovot, Israel

[2] Weizmann Inst Sci, Dept Mol Cell Biol, Rehovot, Israel

[3] Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA

[4] Univ Maryland, Dept Comp Sci, College Pk, MD 20742 USA

[5] NCI, Canc Data Sci Lab, NIH, Bethesda, MD 20892 USA

[6] Weizmann Inst Sci, Dept Vet Resources, Rehovot, Israel

[7] NCBI, Computat Biol & Bioinformat Branch CBB, Natl Lib Med, NIH, Bethesda, MD USA

[8] Edmond & Lily Safra Childrens Hosp, Metab Dis Unit, Sheba Med Ctr, Tel Hashomer, Israel

[9] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel

[10] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

来源：

CANCER RESEARCH | 2019年 / 79卷 / 03期

基金：

以色列科学基金会;

关键词：

DYSREGULATED PH; EXERCISE TEST; CELL-GROWTH; HYPOXIA; GLUTAMINE; AMMONIA; LIVER; GENE;

D O I：

10.1158/0008-5472.CAN-18-1062

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Downregulation of the urea cycle enzyme argininosuccinate synthase (ASS1) by either promoter methylation or by HIF1 alpha is associated with increased metastasis and poor prognosis in multiple cancers. We have previously shown that in normoxic conditions, ASS1 downregulation facilitates cancer cell proliferation by increasing aspartate availability for pyrimidine synthesis by the enzyme complex CAD. Here we report that in hypoxia, ASS1 expression in cancerous cells is downregulated further by HIF1 alpha-mediated induction of miR-224-5p, making the cells more invasive and dependent on upstream substrates of ASS1 for survival. ASS1 was downregulated under acidic conditions, and ASS1-depleted cancer cells maintained a higher intracellular pH (pHi), depended less on extracellular glutamine, and displayed higher glutathione levels. Depletion of substrates of urea cycle enzymes in ASS1-deficient cancers decreased cancer cell survival. Thus, ASS1 levels in cancer are differentially regulated in various environmental conditions to metabolically benefit cancer progression. Understanding these alterations may help uncover specific context-dependent cancer vulnerabilities that may be targeted for therapeutic purposes. Significance: Cancer cells in an acidic or hypoxic environment downregulate the expression of the urea cycle enzyme ASS1, which provides them with a redox and pH advantage, resulting in better survival. [GRAPHICS] .

引用

页码：518 / 533

页数：16

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