Deng Jun-Hao, Li Hong-Yue, Liu Zi-Yang, Liang Jing-Pei, Ren Ying, Zeng Yuan-Ying, Wang Ya-Li, Mao Xin-Liang
The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 511436, China.
Guangdong Provincial Key Laboratory of Protein Modification and Diseases, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
Acta Pharmacol Sin. 2025 Jun;46(6):1733-1741. doi: 10.1038/s41401-025-01481-2. Epub 2025 Feb 12.
Triple negative breast cancer (TNBC) is difficult to treat and novel therapeutic targets remain to be identified. TRIP13, an AAA+ ATPase, is highly expressed in breast cancer and predicts poor prognosis; however, the specific mechanism is not fully understood. In the present study, we found TRIP13 promotes TNBC cell viability and migration. In a mechanistic study, TRIP13 is found to activate STAT3 but not other STAT members. Out of expectation, TRIP13 is found to be upregulated by STAT3 and STAT3 specifically recognizes and binds to the STAT3-recognition element in the regulatory region of TRIP13. Moreover, we found bardoxolone, a recently approved drug for the treatment of chronic kidney disease, displays potent activity by inhibiting STAT3 activation and downregulating TRIP13. Furthermore, bardoxolone inhibits breast cancer cell proliferation and migration, and induces apoptosis. Consistent with this finding, ectopic expression of TRIP13 ablates bardoxolone-induced breast cancer cell apoptosis. Bardoxolone also exerts great activity to suppress TNBC tumor growth in vivo but does not show toxicity. Therefore, we reveal that the TRIP13/STAT3 circuit promotes TNBC cell proliferation and this circuit is a promising target for the treatment of TNBC.
三阴性乳腺癌（TNBC）难以治疗，新型治疗靶点仍有待确定。TRIP13是一种AAA+ATP酶，在乳腺癌中高表达且预示预后不良；然而，其具体机制尚未完全明确。在本研究中，我们发现TRIP13可促进TNBC细胞的活力和迁移。在机制研究中，发现TRIP13可激活STAT3，但不激活其他STAT成员。出乎意料的是，发现TRIP13受STAT3上调，且STAT3特异性识别并结合TRIP13调控区域中的STAT3识别元件。此外，我们发现巴多昔芬（一种最近被批准用于治疗慢性肾病的药物）通过抑制STAT3激活和下调TRIP13发挥强大作用。此外，巴多昔芬抑制乳腺癌细胞增殖和迁移，并诱导凋亡。与此发现一致，TRIP13的异位表达消除了巴多昔芬诱导的乳腺癌细胞凋亡。巴多昔芬在体内也具有强大的抑制TNBC肿瘤生长的作用，但未显示出毒性。因此，我们揭示TRIP13/STAT3环路促进TNBC细胞增殖，并且该环路是治疗TNBC的一个有前景的靶点。
