Neoplasma. 2017;64(6):869-879. doi: 10.4149/neo_2017_608.
Small cell lung cancer (SCLC) is characterized by rapid growth rate and a tendency to metastasize to distinct sites of patients' bodies. The human serine/threonine kinase 33 (STK33) gene has shown its potency as a therapeutic target for prevention of lung carcinomas including non-small cell lung cancer (NSCLC), but its function in the oncogenesis and development of SCLC remains unrevealed. In the current study, it was hypothesized that STK33 played a key role in the proliferation, survival, and invasion of SCLC cells. The expression of STK33 in human SCLC cell lines NCI-H466 and DMS153 was inhibited by specific shRNA. The cell proliferation, cell apoptosis, and cell invasion of the cells were assessed with a series of in vitro assays. To explore the mechanism through which STK33 gene exerted its function in the carcinogenesis of SCLC cells, the effect of STK33 knockdown on the activity of S6K1/RPS6/BAD signaling was detected. Then the results were further confirmed with STK33 inhibitor ML281 and in vivo assays. The results demonstrated that inhibition of STK33 in SCLC cells suppressed the cell proliferation and invasion while induced cell apoptosis. Associated with the change in the phenotypic features, knockdown of STK33 also decreased the phosphorylation of RPS6 and BAD while increased the expression of cleaved caspase 9, indicating that apoptosis induced by STK33 suppression was mediated via mitochondrial pathway. Similar to the results of STK33 knockdown, incubating NCI-H466 cells with STK33 inhibitor also reduced the cell viability by suppressing RPS6/BAD pathways. Additionally, STK33 knockdown also inhibited tumor growth and RPS6/BAD activity in mice models. Findings outlined in our study were different from that in NSCLC to some extent: knockdown of STK33 in SCLC cells induced the apoptosis through mitochondrial pathway but independent of S6K1 function, inferring that the function of STK33 might be cancer type specific.
小细胞肺癌（SCLC）的特征是生长速度快，有向患者身体不同部位转移的倾向。人类丝氨酸/苏氨酸激酶 33（STK33）基因已被证明是预防肺癌（包括非小细胞肺癌[NSCLC]）的有效治疗靶点，但它在 SCLC 发生和发展中的作用尚未揭示。在本研究中，假设 STK33 在 SCLC 细胞的增殖、存活和侵袭中发挥关键作用。通过特异性 shRNA 抑制人 SCLC 细胞系 NCI-H466 和 DMS153 中的 STK33 表达。通过一系列体外实验评估细胞增殖、细胞凋亡和细胞侵袭。为了探讨 STK33 基因在 SCLC 细胞致癌作用中的功能机制，检测了 STK33 敲低对 S6K1/RPS6/BAD 信号活性的影响。然后用 STK33 抑制剂 ML281 和体内实验进一步证实。结果表明，SCLC 细胞中 STK33 的抑制抑制了细胞增殖和侵袭，同时诱导了细胞凋亡。与表型特征的变化相关，STK33 敲低还降低了 RPS6 和 BAD 的磷酸化，同时增加了 cleaved caspase 9 的表达，表明 STK33 抑制诱导的凋亡是通过线粒体途径介导的。与 STK33 敲低的结果相似，用 STK33 抑制剂孵育 NCI-H466 细胞也通过抑制 RPS6/BAD 途径降低了细胞活力。此外，STK33 敲低还抑制了小鼠模型中的肿瘤生长和 RPS6/BAD 活性。我们的研究结果在某种程度上与 NSCLC 的结果不同：SCLC 细胞中 STK33 的敲低通过线粒体途径诱导凋亡，但不依赖于 S6K1 功能，这表明 STK33 的功能可能具有肿瘤类型特异性。
