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Hsp90 inhibition transiently activates Src kinase and promotes Src-dependent Akt and Erk activation

Fumitaka Koga1, Wanping Xu, Tatiana S Karpova

  • 1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 10, Room 1-5940, Bethesda, MD 20892-1107, USA.

Proceedings of the National Academy of Sciences of the United States of America
|July 18, 2006
PubMed

Insights

Heat shock protein 90 (Hsp90) inhibitors like geldanamycin can unexpectedly activate cancer-promoting pathways, including Akt and Erk. This study reveals Hsp90 inhibition triggers Src kinase activation, leading to potential tumor progression and suggesting dual Hsp90/Src inhibition.

Area of Science:

  • Molecular Biology
  • Oncology
  • Signal Transduction

Background:

  • Heat shock protein 90 (Hsp90) stabilizes client proteins, including oncogenic signaling molecules crucial for cancer progression.
  • Hsp90 inhibitors demonstrate antitumor activity by destabilizing these client proteins.
  • Concerns exist regarding Hsp90 inhibitors paradoxically activating pro-tumorigenic pathways like Akt and Erk.

Purpose of the Study:

  • To investigate the mechanism by which the Hsp90 inhibitor geldanamycin activates Akt and Erk signaling.
  • To determine if this activation is dependent on tumor suppressor PTEN status.
  • To explore the therapeutic implications of Hsp90 inhibition, particularly regarding potential pathway activation.

Main Methods:

  • Treatment of cells with geldanamycin, a prototypical Hsp90 inhibitor.
  • Analysis of Akt and Erk phosphorylation status.
  • Investigation of Src kinase activation, Cbl phosphorylation, and phosphatidylinositol 3-kinase (PI3K) recruitment.
  • Assessment of Src-Hsp90 association dynamics.

Main Results:

  • Geldanamycin induces Akt and Erk activation independently of PTEN status.
  • This activation is mediated by transient Src kinase activation, which phosphorylates Cbl, leading to PI3K activation.
  • Geldanamycin treatment rapidly disrupts the association between Src and Hsp90, suggesting Src activation stems from chaperone dissociation.

Conclusions:

  • Hsp90 inhibition by geldanamycin can lead to pro-tumorigenic Akt and Erk activation via Src kinase.
  • The mechanism involves the dissociation of Src from Hsp90, facilitating downstream signaling.
  • Dual inhibition of Hsp90 and Src may be a beneficial therapeutic strategy in certain cancer contexts.

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