Thoracic Surgery Department, West China Hospital, Sichuan University School of Medicine, Chengdu Sichuan Province 610041, China.
Lung Cancer. 2011 Mar;71(3):291-7. doi: 10.1016/j.lungcan.2010.06.004.
Cisplatin [cis-diaminodichloroplatinum (II) (CDDP)] is the cornerstone of lung cancer chemotherapy. However, its efficacy is limited due to the development of drug resistance in cancer cells. This study was designed to uncover the mechanisms under CDDP resistance in lung cancer cells involving endoplasmic reticulum (ER) stress tolerance-induced and GRP78-dependant Akt activation. In this study we established ER stress-tolerant (ERST) human lung cancer lines H460et and A549et. We found that the ERST Lung cancer cells are resistant to CDDP treatment. We further showed that, compared to the parental cell lines, H460et and A549et show significantly increased GRP78 and phospho(p)-Akt levels. And phosphorylation of Akt, which can be regulated by GRP78, is essential to the ERST-associated CDDP resistance. Our findings identify a new mechanism of regulating Akt activity and a new mechanism through which CDDP resistance is formed in lung cancer cells.
顺铂[顺式-二氨二氯铂(II)（CDDP）]是肺癌化疗的基石。然而，由于癌细胞产生耐药性，其疗效受到限制。本研究旨在揭示涉及内质网（ER）应激耐受诱导和 GRP78 依赖性 Akt 激活的肺癌细胞中 CDDP 耐药的机制。在这项研究中，我们建立了内质网应激耐受（ERST）人肺癌细胞系 H460et 和 A549et。我们发现，与亲本细胞系相比，H460et 和 A549et 显示出明显增加的 GRP78 和磷酸化（p）-Akt 水平。Akt 的磷酸化可以被 GRP78 调节，这对于 ERST 相关的 CDDP 耐药性是必不可少的。我们的研究结果确定了调节 Akt 活性的新机制，以及肺癌细胞中形成 CDDP 耐药性的新机制。
