Compromising the constitutive p16INK4a expression sensitizes human neuroblastoma cells to Hsp90 inhibition and promotes premature senescence

Abhijnya Vijayavittal Kanugovi, Chitra Joseph, Satish Siripini, Khanderao Paithankar, Sreedhar Subbarao Amere*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The Hsp90 chaperone has become the attractive pharmacological target to inhibit tumor cell proliferation. However, tumor cells can evolve with mechanisms to overcome Hsp90 inhibition. Using human neuroblastoma, we have investigated one such limitation. Here, we demonstrate that neuroblastoma cells overcome the interference of tumor suppressor p16INK4a in cell proliferation, which is due to its latent interaction with CDK4 and CDK6. Cells also displayed impedance to the pharmacological inhibition of cancer chaperone Hsp90 inhibition with respect to induced cytotoxicity. However, the p16INK4a knockdown has triggered the activation of cyclin-CDK6 axis and enhanced the cell proliferation. These cells are eventually sensitized to Hsp90 inhibition by activating the DNA damage response mediated through p53-p21WAF-1 axis and G1 cell cycle exit. While both CDK4 and CDK6 have exhibited low affinity to p16INK4a, CDK6 has exhibited high affinity to Hsp90. Destabilizing the CDK6 interaction with Hsp90 has prolonged G2/M cell cycle arrest fostering to premature cellular senescence. The senescence driven cells exhibited compromised metastatic potential both in vitro as well as in mice xenografts. Our study unravels that cancer cells can be adapted to the constitutive expression of tumor suppressors to overcome therapeutic interventions. Our findings display potential implication of Hsp90 inhibitors to overcome such adaptations.

Original languageEnglish
Pages (from-to)2770-2781
Number of pages12
JournalJournal of Cellular Biochemistry
Volume121
Issue number4
Early online date6 Nov 2019
DOIs
Publication statusPublished - Apr 2020

Keywords

  • 17AAG
  • cancer
  • Hsp90
  • p16INK4a
  • senescence
  • tumor suppressor

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