Tsai Chia-Lung, Chao Angel, Jung Shih-Ming, Tsai Chi-Neu, Lin Chiao-Yun, Chen Shun-Hua, Sue Shih-Che, Wang Tzu-Hao, Wang Hsin-Shih, Lai Chyong-Huey
Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
Oncotarget. 2016 Aug 2;7(31):50548-50563. doi: 10.18632/oncotarget.10500.
Overexpression of stress-induced phosphoprotein 1 (STIP1) - a co-chaperone of heat shock protein (HSP) 70/HSP90 - and activation of the JAK2-STAT3 pathway occur in several tumors. Combined treatment with a HSP90 inhibitor and a JAK2 inhibitor exert synergistic anti-cancer effects. Here, we show that STIP1 stabilizes JAK2 protein in ovarian and endometrial cancer cells. Knock-down of endogenous STIP1 decreased JAK2 and phospho-STAT3 protein levels. The N-terminal fragment of STIP1 interacts with the N-terminus of JAK2, whereas the C-terminal DP2 domain of STIP1 mediates the interaction with HSP90 and STAT3. A peptide fragment in the DP2 domain of STIP1 (peptide 520) disrupted the interaction between STIP1 and HSP90 and induced cell death through JAK2 suppression. In an animal model, treatment with peptide 520 inhibited tumor growth. In summary, STIP1 modulates the function of the HSP90-JAK2-STAT3 complex. Peptide 520 may have therapeutic potential in the treatment of JAK2-overexpressing tumors.
应激诱导磷蛋白1（STIP1）——热休克蛋白（HSP）70/HSP90的一种共伴侣分子——的过表达以及JAK2-STAT3信号通路的激活在多种肿瘤中均有发生。HSP90抑制剂与JAK2抑制剂联合治疗具有协同抗癌作用。在此，我们发现STIP1可使卵巢癌和子宫内膜癌细胞中的JAK2蛋白稳定。敲低内源性STIP1可降低JAK2和磷酸化STAT3蛋白水平。STIP1的N端片段与JAK2的N端相互作用，而STIP1的C端DP2结构域介导与HSP90和STAT3的相互作用。STIP1的DP2结构域中的一个肽段（肽段520）破坏了STIP1与HSP90之间的相互作用，并通过抑制JAK2诱导细胞死亡。在动物模型中，肽段520治疗可抑制肿瘤生长。总之，STIP1调节HSP90-JAK2-STAT3复合物的功能。肽段520在治疗JAK2过表达肿瘤方面可能具有治疗潜力。
