Targeted inhibition of MASTL kinase activity induces apoptosis in breast cancer

Misra, Gauri; Rajawat, Jyotika; Pal, Rajesh; Smith, Jeremy C.; Kumar, Amit

doi:10.1016/j.lfs.2023.122250

Title: Targeted inhibition of MASTL kinase activity induces apoptosis in breast cancer

Journal Article · 04 November 2023 · Life Sciences

DOI: https://doi.org/10.1016/j.lfs.2023.122250 · OSTI ID:2426045

Misra, Gauri ^[1]; Rajawat, Jyotika ^[2]; Pal, Rajesh ^[3];

^[4]; Kumar, Amit ^[5]

National Institute of Biologicals, Noida (India)
University of Lucknow (India)
German Cancer Research Centre (DKFZ), Heidelberg (Germany)
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)
Univ. of Cagliari (Italy)

Microtubule-associated serine/threonine kinase-like (MASTL) (or Greatwall kinase (GWL)) is an important cell cycle regulating kinase that regulates the G2-M transition. Uncontrolled MASTL activity is implicated in breast cancer progression. To date, very few inhibitors have been reported against this protein. Here, structure-based computational modeling indicates that the natural product flavopiridol (FLV) binds strongly to MASTL and these results are validated using molecular dynamics simulation studies. Further, an in vitro kinase assay reveals an EC₅₀ (effective concentration) value of FLV to be 82.1 nM and a better IC₅₀ compared to the positive reference compound, staurosporine. FLV is found to inhibit MASTL kinase activity, arresting the cell growth in the G1 phase and inducing apoptosis in breast cancer cells. Consistent with these results differential gene expression obtained using RNA sequencing studies, and validated by RT PCR and immunoblot analysis, indicate that MASTL inhibition induces cell cycle arrest and apoptotic-related genes. Furthermore, metastasis- and inflammation- related genes are downregulated. Thus, the deregulation of MASTL signaling pathways on targeted inhibition of its kinase activity is revealed. This study lays a strong foundation for investigating FLV as a lead compound in breast cancer therapeutics.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 2426045

Journal Information:: Life Sciences, Journal Name: Life Sciences Vol. 334; ISSN 0024-3205

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
Breast cancer
Flavopiridol
In silico
In vitro
Kinase assay
MASTL

Title: Targeted inhibition of MASTL kinase activity induces apoptosis in breast cancer

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References (48)

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