Shanmugam Muthu K, Rajendran Peramaiyan, Li Feng, Kim Chulwon, Sikka Sakshi, Siveen Kodappully Sivaraman, Kumar Alan Prem, Ahn Kwang Seok, Sethi Gautam
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Department of Oriental Pathology, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea.
Mol Carcinog. 2015 Oct;54(10):971-85. doi: 10.1002/mc.22166. Epub 2014 May 3.
Persistent activation of signal transducer and activator of transcription 3 (STAT3) is one of the characteristic features of renal cell carcinoma (RCC) and often linked to its deregulated proliferation, survival, and angiogenesis. In the present report, we investigated whether zerumbone, a sesquiterpene, exerts its anticancer effect through modulation of STAT3 activation pathway. The pharmacological effect of zerumbone on STAT3 activation, associated protein kinases and phosphatase, and apoptosis was investigated using both RCC cell lines and xenograft mouse model. We observed that zerumbone suppressed STAT3 activation in a dose- and time-dependent manner in RCC cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src, Janus-activated kinase 1, and Janus-activated kinase 2. Pervanadate treatment reversed zerumbone-induced downregulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that zerumbone induced the expression of tyrosine phosphatase SHP-1 that correlated with its ability to inhibit STAT3 activation. Interestingly, deletion of SHP-1 gene by siRNA abolished the ability of zerumbone to inhibit STAT3 activation. The inhibition of STAT3 activation by zerumbone also caused the suppression of the gene products involved in proliferation, survival, and angiogenesis. Finally, when administered i.p., zerumbone inhibited STAT3 activation in tumor tissues and the growth of human RCC xenograft tumors in athymic nu/nu mice without any side effects. Overall, our results suggest for the first time that zerumbone is a novel blocker of STAT3 signaling cascade and thus has an enormous potential for the treatment of RCC and other solid tumors.
信号转导与转录激活因子3（STAT3）的持续激活是肾细胞癌（RCC）的特征之一，且常与其增殖失调、存活及血管生成相关。在本报告中，我们研究了倍半萜姜黄二酮是否通过调节STAT3激活途径发挥其抗癌作用。利用RCC细胞系和异种移植小鼠模型研究了姜黄二酮对STAT3激活、相关蛋白激酶和磷酸酶以及细胞凋亡的药理作用。我们观察到姜黄二酮在RCC细胞中以剂量和时间依赖性方式抑制STAT3激活。这种抑制是通过抑制上游激酶c-Src、Janus激活激酶1和Janus激活激酶2的激活介导的。过钒酸盐处理逆转了姜黄二酮诱导的STAT3下调，提示酪氨酸磷酸酶参与其中。事实上，我们发现姜黄二酮诱导酪氨酸磷酸酶SHP-1的表达，这与其抑制STAT3激活的能力相关。有趣的是，通过小干扰RNA（siRNA）缺失SHP-1基因消除了姜黄二酮抑制STAT3激活的能力。姜黄二酮对STAT3激活的抑制也导致了参与增殖、存活和血管生成的基因产物的抑制。最后，腹腔注射姜黄二酮可抑制无胸腺裸鼠肿瘤组织中的STAT3激活以及人RCC异种移植肿瘤的生长，且无任何副作用。总体而言，我们的结果首次表明姜黄二酮是STAT3信号级联的新型阻断剂，因此在治疗RCC和其他实体瘤方面具有巨大潜力。
