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PLK1 and AURKB phosphorylate survivin differentially to affect proliferation in racially distinct triple-negative

Chakravarthy Garlapati1,2, Shriya Joshi2, Shristi Bhattarai2

  • 1Alkermes Inc, Waltham, MA, 02451, USA.

Cell Death & Disease
|January 10, 2023
PubMed

Insights

Targeting survivin phosphorylation with PLK1 and AURKB inhibitors shows promise for African American triple-negative breast cancer (TNBC) patients. This approach specifically suppresses tumor growth in AA TNBC by inhibiting key kinases involved in cell proliferation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Disparities

Background:

  • Protein diversity through alternative mRNA splicing and post-translational modifications (PTMs) is crucial for cellular functions.
  • Mitotic kinases Polo-like Kinase 1 (PLK1) and Aurora B (AURKB) phosphorylate survivin, regulating cell proliferation.
  • PLK1, AURKB, and survivin are overexpressed in triple-negative breast cancer (TNBC), a highly aggressive subtype.

Purpose of the Study:

  • To investigate the role of survivin phosphorylation in racial disparities observed in TNBC cell proliferation.
  • To determine if targeting PLK1 and AURKB offers a differential therapeutic strategy for African American (AA) versus European American (EA) TNBC patients.

Main Methods:

  • Analysis of TCGA TNBC data to compare PLK1 and AURKB expression levels between AA and EA patients.
  • Assessment of survivin phosphorylation (p-survivin) levels in AA and EA TNBC cells.
  • Functional studies involving survivin silencing via small interfering RNAs (siRNAs).
  • Inhibition of PLK1 and AURKB using volasertib and barasertib in TNBC xenograft models.

Main Results:

  • Higher expression of PLK1 and AURKB was observed in AA TNBC patients compared to EA TNBC patients.
  • AA TNBC cells exhibited significantly higher p-survivin levels than EA TNBC cells.
  • Survivin silencing attenuated proliferation and cell cycle progression specifically in AA TNBC cells.
  • Inhibition of PLK1 and AURKB significantly suppressed tumor growth in AA TNBC xenografts but not in EA TNBC tumors.

Conclusions:

  • Survivin phosphorylation plays a critical role in the heightened proliferation of AA TNBC.
  • Targeting PLK1 and AURKB demonstrates a specific therapeutic efficacy in AA TNBC models.
  • Inhibition of PLK1 and AURKB represents a potential targeted therapy for African American patients with triple-negative breast cancer.

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