主页 > 生命科学 >
【medical-news】肿瘤细胞信号——按最爽的途径生
Nature Reviews Cancer 8, 484-485 (July 2008) | doi:10.1038/nrc2424
Katharine H. Wrighton
Response rates to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in cancer treatment have been surprisingly and disappointingly low. Zhang Weihua and colleagues now shed some light on this issue by revealing a kinase-independent function of EGFR in maintaining cell survival.
Using prostate, breast and colon cancer cells the authors demonstrated that small interfering RNA (siRNA)-mediated knockdown of EGFR, but not inhibition of EGFR kinase activity, leads to autophagic cell death. Autophagy can occur when external energy sources are low or unobtainable and, although glucose levels remained constant in cells treated with kinase inhibitors, they were decreased by around 50% in cells transfected with EGFR siRNA.
So, how does EGFR maintain intracellular glucose levels? Data indicate that EGFR expression can alter glucose uptake, and the authors also found that expression of the sodium and glucose cotransporter SGLT1 was undetectable in cells treated with EGFR siRNA compared with controls. Moreover, knockdown of SGLT1 directly mimicked EGFR siRNA-mediated autophagy. Downregulation of SGLT1 in the absence of EGFR could be rescued by inhibiting proteasome activity, implying that SGLT1 is degraded in response to the loss of EGFR expression. Importantly, SGLT1 was found to interact with wild-type and a kinase-deficient EGFR, and SGLT1 levels were preserved in cells transfected with EGFR siRNA and siRNA-resistant wild-type or kinase-deficient EGFR constructs. These findings suggest that EGFR stabilizes SGLT1 independently of its kinase activity.
Finally, the authors tested the glucose starvation sensitivity of cancer cells expressing varying levels of EGFR. Cancer cells that express EGFR also expressed SGLT1 and were resistant to glucose starvation-induced cell death. Conversely, cancer cells lacking EGFR did not express SGLT1 and could not survive in physiological glucose concentrations, although overexpression of EGFR or SGLT1 enhanced their survival even in low glucose.
This study reveals that EGFR–SGLT1 may confer a survival advantage to cancer cells by maintaining a basal level of intracellular glucose and preventing autophagy. This may help to explain previous data indicating that inhibition of EGFR kinase activity is not sufficient to induce cell death, or to negate all of the functions of EGFR. Targeting both kinase-dependent and kinase-independent functions of EGFR may be necessary for more successful therapy in the future.
http://www.nature.com/nrc/journal/v8/n7/full/nrc2424.html 本人已认领该文编译，48小时后若未提交译文，请其他战友自由认领。 Signalling: Survival of the sweetest
肿瘤细胞信号——走最甜的路（这里的sweetest用的真好，感觉有双关的意思，看完了就明白了）
Response rates to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in cancer treatment have been surprisingly and disappointingly low. Zhang Weihua and colleagues now shed some light on this issue by revealing a kinase-independent function of EGFR in maintaining cell survival.
EGFR酪氨酸激酶抑制剂在肿瘤的治疗中的反应率是出乎意料和令人失望的低。最近，Zhang Weihua 及期同事发现了EGFR独立于激酶之外维持细胞生存的功能，为深入理解这个问题带了一缕曙光。
Using prostate, breast and colon cancer cells the authors demonstrated that small interfering RNA (siRNA)-mediated knockdown of EGFR, but not inhibition of EGFR kinase activity, leads to autophagic cell death. Autophagy can occur when external energy sources are low or unobtainable and, although glucose levels remained constant in cells treated with kinase inhibitors, they were decreased by around 50% in cells transfected with EGFR siRNA.
用前列腺，乳腺癌和大肠癌肿瘤细胞作为研究对象，作者发现不是抑制EGFR激酶活性，而是用siRNA沉默EGFR，能诱导自噬性细胞死亡。细胞会出现自噬性细胞死亡，是因为当外源性能量低下或不足时，虽然在酪氨酸激酶抑制剂治疗中，细胞内葡萄糖水平保持稳定，但在EGFR siRNA 转染的细胞中，细胞内葡萄糖水平下降了大约50%。
So, how does EGFR maintain intracellular glucose levels? Data indicate that EGFR expression can alter glucose uptake, and the authors also found that expression of the sodium and glucose cotransporter SGLT1 was undetectable in cells treated with EGFR siRNA compared with controls.
那么， EGFR是如何维持细胞内葡萄糖水平？研究结果提示EGFR的表达能改变细胞葡萄糖的摄入，作者发现钠和糖共同转运载体 SGLT1与对照相比，在EGFR siRNA处理的细胞中检测不到。
Moreover, knockdown of SGLT1 directly mimicked EGFR siRNA-mediated autophagy. Downregulation of SGLT1 in the absence of EGFR could be rescued by inhibiting proteasome activity, implying that SGLT1 is degraded in response to the loss of EGFR expression. Importantly, SGLT1 was found to interact with wild-type and a kinase-deficient EGFR, and SGLT1 levels were preserved in cells transfected with EGFR siRNA and siRNA-resistant wild-type or kinase-deficient EGFR constructs. These findings suggest that EGFR stabilizes SGLT1 independently of its kinase activity.
阅读本文的人还阅读：
作者:admin@医学,生命科学 2010-11-05 05:11
医学,生命科学网