Mechanism of abnormality in p27^<K1P1> expression in human lung cancer and its therapeutic application

我们之前的一项研究意外地发现，与非小细胞肺癌（NSCLC）与不良预后相关的频繁减少相反，p27^<K1P1>细胞周期蛋白依赖性激酶（CDK）抑制剂在几乎所有的小细胞肺癌（SCLCs）中都保持高表达，这代表了最具侵袭性的肺癌形式。这一观察结果表明，SCLC中高表达的p27^<K1P1>可能是无功能的，可能是由于这种肿瘤类型的多种遗传缺陷。然而，生化分析显示p27^<K1P1>在SCLC中具有CDK抑制剂的功能，清楚地显示出与G1/G0阻滞和有效抑制细胞周期蛋白-CDK激酶活性明显相关的诱导。有趣的是，我们可以证明p27^<K1P1>的诱导赋予SCLC细胞在缺乏营养和缺氧等不利于细胞生长的培养条件下存活的能力。随后的p27^<K1P1>转染实验支持了这一观点。这些观察结果表明，体内p27^<K1P1>的高表达可能通过在不利于细胞增殖的微环境中阻止细胞凋亡而有利于SCLC的存活。

A previous study of ours unexpectedly found that in contrast to frequent reduction in non-small cell lung cancer (NSCLC) in association with poor prognosis, high expression of the p27^<K1P1> cyclin-dependent kinase (CDK) inhibitor was retained in virtually all small cell lung cancers (SCLCs), which represent the most aggressive form of lung cancer. This observation suggested the possibility that highly expressed p27^<K1P1> in SCLC may be non-functional, possibly due to multiple genetic defects in this tumor type. Biochemical analyses, however, revealed that p27^<K1P1> in SCLC is functional aas a CDK inhibitor, clearly showing induction apparently associated with G1/G0 arrest and efficient inhibition of cyclin-CDK kinase activities. Interestingly, we could show that induction of p27^<K1P1> confers on SCLC cells the ability to survive under culture conditions unfavorable for cell growth such as a lack of nutrients and hypoxia. Subsequent transfection experiments with p27^<K1P1> supported this notion. These obsevations suggest that high expression of p27^<K1P1> in vivo may favor the survival of SCLC by preventing apoptosis in a microenvironment unfavorable for cell proliferation.