SIK2 is a centrosome kinase required for bipolar mitotic spindle formation that provides a potential target for therapy in ovarian cancer

Cancer Cell. 2010 Aug 9;18(2):109-21. doi: 10.1016/j.ccr.2010.06.018.

Abstract

Regulators of mitosis have been successfully targeted to enhance response to taxane chemotherapy. Here, we show that the salt inducible kinase 2 (SIK2) localizes at the centrosome, plays a key role in the initiation of mitosis, and regulates the localization of the centrosome linker protein, C-Nap1, through S2392 phosphorylation. Interference with the known SIK2 inhibitor PKA induced SIK2-dependent centrosome splitting in interphase while SIK2 depletion blocked centrosome separation in mitosis, sensitizing ovarian cancers to paclitaxel in culture and in xenografts. Depletion of SIK2 also delayed G1/S transition and reduced AKT phosphorylation. Higher expression of SIK2 significantly correlated with poor survival in patients with high-grade serous ovarian cancers. We believe these data identify SIK2 as a plausible target for therapy in ovarian cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology
  • Cell Cycle / drug effects
  • Centrosome / enzymology*
  • Female
  • Humans
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / therapy*
  • Paclitaxel / pharmacology
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering
  • Spindle Apparatus*
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents, Phytogenic
  • RNA, Small Interfering
  • salt-inducible kinase-2, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Paclitaxel