Fdel Azeza M, Waters Loren, Sharma Ira, Jones Samuel, Gee Julia, Atack John R, Banerjee Sourav, Mehellou Youcef
Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, U.K.
Medicines Discovery Institute, Cardiff University, Cardiff CF10 3AT, U.K.
ACS Pharmacol Transl Sci. 2025 Feb 27;8(3):726-735. doi: 10.1021/acsptsci.4c00603. eCollection 2025 Mar 14.
The protein kinase OSR1 has been highlighted as a biomarker for a poor prognosis in breast cancer (BC) patients. To further decipher the mechanism underpinning this, we studied the expression, phosphorylation status, and catalytic activity of OSR1 across a series of BC cell lines. OSR1 was found to be expressed across the various luminal and triple negative BC (TNBC) cell lines studied, although it was only constitutively active in the highly migratory TNBC cell line MDA-MB-231. Although this cell line carries p53 mutations, our data indicated that OSR1 constitutive kinase activity of the OSR1 in MDA-MB-231 was independent of p53. Interestingly, the inhibition of OSR1 had no significant impact on MDA-MB-231 cell viability, but it was found to contribute to its substantial cell migration and invasion, as this was significantly attenuated by the WNK/OSR1 inhibitor WNK463. Analogously, the overexpression of constitutively active OSR1 in the poorly migrating BC cell line MCF7 enhanced its cell mobility. Collectively, our results indicate that the pharmacological inhibition of OSR1 could be a promising novel strategy for preventing the oncogenic potential of TNBC.
蛋白激酶OSR1已被视为乳腺癌（BC）患者预后不良的生物标志物。为了进一步阐明其潜在机制，我们研究了一系列BC细胞系中OSR1的表达、磷酸化状态和催化活性。在所研究的各种腔面型和三阴性乳腺癌（TNBC）细胞系中均发现了OSR1的表达，不过它仅在高迁移性的TNBC细胞系MDA-MB-231中组成性激活。尽管该细胞系携带p53突变，但我们的数据表明MDA-MB-231中OSR1的组成性激酶活性独立于p53。有趣的是，抑制OSR1对MDA-MB-231细胞活力没有显著影响，但发现它有助于其大量的细胞迁移和侵袭，因为WNK/OSR1抑制剂WNK463可显著减弱这种迁移和侵袭。类似地，在迁移能力较差的BC细胞系MCF7中组成性激活的OSR1的过表达增强了其细胞迁移能力。总体而言，我们的结果表明，对OSR1进行药理抑制可能是预防TNBC致癌潜力的一种有前景的新策略。
