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The ATM and ATR kinases regulate centrosome clustering and tumor recurrence by targeting KIFC1 phosphorylation

Guangjian Fan1, Lianhui Sun1, Ling Meng2

  • 1Translational Medicine Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 201620, Shanghai, China.

Nature Communications
|January 5, 2021
PubMed

Insights

Centrosome amplification drives cancer recurrence and drug resistance. This study reveals KIFC1 phosphorylation by ATM/ATR kinases promotes survival of cancer cells with amplified centrosomes, suggesting KIFC1 inhibition as a therapeutic strategy.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Molecular Oncology

Background:

  • Drug resistance and tumor recurrence are significant obstacles in cancer treatment.
  • Cancer cells frequently exhibit centrosome amplification, a condition where cells possess more than two centrosomes.
  • Centrosome clustering enables cancer cells with supernumerary centrosomes to undergo bipolar division, promoting survival and proliferation.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of centrosome clustering in cancer cells.
  • To investigate the role of KIFC1 (kinesin family member C1) in centrosome clustering and its association with tumor recurrence.
  • To explore the potential of targeting KIFC1 phosphorylation as a therapeutic strategy against drug-resistant cancers.

Main Methods:

  • Investigated the association between KIFC1 expression and tumor recurrence.
  • Examined the phosphorylation of KIFC1 at Ser26 by ATM and ATR kinases under DNA damaging conditions.
  • Assessed the effect of KIFC1 phosphorylation inhibition on centrosome clustering, cancer cell survival, drug resistance, and tumor recurrence in preclinical models.

Main Results:

  • KIFC1 was found to be positively associated with tumor recurrence in cancer.
  • DNA damaging treatments induced ATM/ATR-mediated phosphorylation of KIFC1 at Ser26, which selectively promoted the survival of cancer cells with amplified centrosomes.
  • Inhibition of KIFC1 phosphorylation effectively repressed centrosome clustering, leading to decreased drug resistance and tumor recurrence.

Conclusions:

  • KIFC1 acts as a crucial regulator of centrosome clustering and is a prognostic marker for tumor recurrence.
  • Cancer cells can acquire therapeutic resistance and recurrence by activating centrosome clustering under DNA damage stress.
  • Targeting KIFC1 phosphorylation presents a promising new therapeutic avenue for overcoming drug resistance and preventing tumor recurrence in cancer patients.

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