Oxidative Stress-Responsive 1 Kinase Catalytic Activity Promotes Triple Negative Breast Cancer Oncogenic Potential

TY - JOUR

T1 - Oxidative Stress-Responsive 1 Kinase Catalytic Activity Promotes Triple Negative Breast Cancer Oncogenic Potential

AU - Fdel, Azeza M.

AU - Waters, Loren

AU - Sharma, Ira

AU - Jones, Samuel

AU - Gee, Julia

AU - Atack, John R.

AU - Banerjee, Sourav

AU - Mehellou, Youcef

PY - 2025/3/14

Y1 - 2025/3/14

N2 - 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.

AB - 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.

KW - OSR1

KW - breast

KW - cancer

KW - inhibitor

KW - migration

UR - https://www.scopus.com/pages/publications/86000434926

U2 - 10.1021/acsptsci.4c00603

DO - 10.1021/acsptsci.4c00603

M3 - Article

C2 - 40109757

SN - 2575-9108

VL - 8

SP - 726

EP - 735

JO - ACS Pharmacology and Translational Science

JF - ACS Pharmacology and Translational Science

IS - 3

ER -