8-Chloroadenosine Sensitivity in Renal Cell Carcinoma Is Associated with AMPK Activation and mTOR Pathway Inhibition.
8-Chloroadenosine Sensitivity in Renal Cell Carcinoma Is Associated with AMPK Activation and mTOR Pathway Inhibition.
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DOI：
10.1371/journal.pone.0135962
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Zurita AJ
中科院分区：
文献类型：
--
作者：
Kearney AY;Fan YH;Giri U;Saigal B;Gandhi V;Heymach JV;Zurita AJ
腺苷类似物8-氯腺苷已被证明消耗ATP并抑制血液恶性肿瘤以及肺癌和乳腺癌细胞系中的肿瘤生长。我们研究了8-氯腺苷对透明细胞（cc）肾细胞癌（RCC）细胞系的影响。8-氯腺苷在体外对ccRCC细胞活力有效，IC 50范围为2 μM（最敏感的CAKI-1）至36 μM（最耐药的RXF-393）。通过反相蛋白质阵列的蛋白质组学分析显示，8-氯腺苷处理导致mTOR途径的抑制。在时间进程的实验中，8-氯腺苷治疗迅速激活AMPK，测量AMPK和ACC磷酸化，随后引起敏感细胞系中的p70 S6 K和核糖体蛋白RPS 6的去磷酸化。然而，在耐药细胞系中，AMPK活性和mTOR通路不受治疗的影响。我们还注意到抗性细胞系具有升高的磷酸RPS 6和AKT基础水平。PI 3 K途径的抑制增强了8-氯腺苷在所有细胞系中的功效。我们的观察结果表明，8-氯腺苷活性与mTOR通路的抑制有关，磷酸RPS 6和PI 3 K通路的激活状态可能决定耐药性。在实体瘤中，RCC是少数对mTOR抑制敏感的肿瘤之一。因此，我们推断，8-氯腺苷可能是有效的RCC激活AMPK和抑制mTOR通路。
The adenosine analog 8-chloroadenosine has been shown to deplete ATP and inhibit tumor growth in hematological malignancies as well as in lung and breast cancer cell lines. We investigated effects of 8-chloroadenosine on clear cell (cc) renal cell carcinoma (RCC) cell lines. 8-chloroadenosine was effective against ccRCC cell viability in vitro, with IC50 ranging from 2 μM in the most sensitive CAKI-1 to 36 μM in the most resistant RXF-393. Proteomic analysis by reverse-phase protein array revealed that 8-chloroadenosine treatment leads to inhibition of the mTOR pathway. In time-course experiments, 8-chloroadenosine treatment rapidly activated AMPK, measured by AMPK and ACC phosphorylation, and subsequently caused dephosphorylation of p70S6K and ribosomal protein RPS6 in the sensitive cell lines. However, in the resistant cell lines, AMPK activity and the mTOR pathway were unaffected by the treatment. We also noted that the resistant cell lines had elevated basal levels of phospho RPS6 and AKT. Inhibition of PI3K pathway enhanced the efficacy of 8-chloroadenosine across all cell lines. Our observations indicate that 8-chloroadenosine activity is associated with inhibition of the mTOR pathway, and that phospho RPS6 and PI3K pathway activation status may determine resistance. Among solid tumors, RCC is one of the few susceptible to mTOR inhibition. We thus infer that 8-chloroadenosine may be effective in RCC by activating AMPK and inhibiting the mTOR pathway.