Kim Hye-Youn, Kim Young-Mi, Hong Suntaek
Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine, Incheon, 21999, Republic of Korea.
Cell Death Discov. 2024 Apr 22;10(1):185. doi: 10.1038/s41420-024-01956-x.
Distant metastasis is a significant hallmark affecting to the high death rate of patients with triple-negative breast cancer (TNBC). Thus, it is crucial to identify and develop new therapeutic strategies to hinder cancer metastasis. While emerging studies have hinted a pivotal role of glucose-regulated protein 94 (GRP94) in tumorigenesis, the exact biological functions and molecular mechanisms of GRP94 in modulating cancer metastasis remain to be elucidated. Our study demonstrated an increased expression of GRP94 in TNBC correlated with metastatic progression and unfavorable prognosis in patients. Functionally, we identified that GRP94 depletion significantly diminished TNBC tumorigenesis and subsequent lung metastasis. In contrast, GRP94 overexpression exacerbated the invasiveness, migration, and lung metastasis of non-TNBC cells. Mechanistically, we found that casein kinase 2 alpha (CK2α) active in advanced breast cancer phosphorylated GRP94 at a conserved serine 306 (S306) residue. This phosphorylation increased the stability of GRP94 and enhanced its interaction with LRP6, leading to activation of canonical Wnt signaling. From a therapeutic standpoint, we found that benzamidine, a novel CK2α inhibitor, effectively suppressed GRP94 phosphorylation, LRP6 stabilization, and metastasis of TNBC. Our results point to the critical role of CK2α-mediated GRP94 phosphorylation in TNBC metastasis through activation of Wnt signaling, highlighting GRP94 as a therapeutic target to impede TNBC metastasis.
远处转移是影响三阴性乳腺癌（TNBC）患者高死亡率的一个重要标志。因此，识别和开发新的治疗策略以阻止癌症转移至关重要。虽然新兴研究暗示葡萄糖调节蛋白94（GRP94）在肿瘤发生中起关键作用，但GRP94在调节癌症转移中的具体生物学功能和分子机制仍有待阐明。我们的研究表明，TNBC中GRP94的表达增加与患者的转移进展和不良预后相关。在功能上，我们发现GRP94的缺失显著减少了TNBC的肿瘤发生和随后的肺转移。相反，GRP94的过表达加剧了非TNBC细胞的侵袭性、迁移和肺转移。从机制上讲，我们发现晚期乳腺癌中活跃的酪蛋白激酶2α（CK2α）在保守的丝氨酸306（S306）残基处磷酸化GRP94。这种磷酸化增加了GRP94的稳定性，并增强了其与低密度脂蛋白受体相关蛋白6（LRP6）的相互作用，导致经典Wnt信号通路的激活。从治疗角度来看，我们发现新型CK2α抑制剂苯甲脒可有效抑制GRP94磷酸化、LRP6稳定化以及TNBC的转移。我们的结果表明CK2α介导的GRP94磷酸化通过激活Wnt信号通路在TNBC转移中起关键作用，突出了GRP94作为阻碍TNBC转移的治疗靶点。
