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HSP90α and KLK6 Co-Regulate Stress-Induced Prostate Cancer Cell Motility.

Katelyn L O'Neill1, Johnny W Zigmond1, Raymond Bergan1,2

  • 1Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.

Biorxiv : the Preprint Server for Biology
|January 9, 2026
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Summary
This summary is machine-generated.

Cellular stress surprisingly decreases matrix metalloproteinase-2 (MMP-2) activity in prostate cancer cells. Extracellular heat shock protein 90α (eHSP90α) is crucial for restoring MMP-2 activity after kallikrein-related peptidase 6 (KLK6) is inhibited.

Keywords:
Cell MotilityHSP90αKLK6MMP-2Prostate CancerStress

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Prostate cancer (PCa) metastasis is regulated by proteases like matrix metalloproteinase-2 (MMP-2).
  • Increased extracellular heat shock protein 90α (eHSP90α) correlates with higher MMP-2 activity, but its role under cellular stress is unclear.

Purpose of the Study:

  • To investigate the impact of cellular stress on extracellular heat shock protein 90α (eHSP90α) and matrix metalloproteinase-2 (MMP-2) activity in prostate cancer.
  • To elucidate the mechanisms regulating MMP-2 activity and cell motility under stress conditions.

Main Methods:

  • Human prostate cell lines were subjected to stress, and eHSP90α levels were measured by immunoblot.
  • MMP activity was assessed using fluorometric gelatin dequenching and zymography.
  • Cell motility was quantified via wound healing and Matrigel invasion assays.
  • CRISPR/Cas9 was used to create HSP90α knockout cells for further validation.

Main Results:

  • Stress increased eHSP90α in all tested prostate cell lines but decreased MMP-2 activity.
  • Conditioned media from stressed cells reduced non-stressed cell motility.
  • Aprotinin, a serine protease inhibitor, rescued MMP-2 activity, but this effect was lost in HSP90α knockout cells.
  • Kallikrein-related peptidase 6 (KLK6) was identified as a stress-induced protease that decreases MMP-2 activity; its knockdown restored MMP-2 activity and cell motility.

Conclusions:

  • A novel stress-induced extracellular network regulates MMP-2 activity and prostate cancer cell motility.
  • Kallikrein-related peptidase 6 (KLK6) is a key stress-induced protease that reduces MMP-2 activity and invasion.
  • Extracellular heat shock protein 90α (eHSP90α) plays a critical role in rescuing MMP-2 activity upon KLK6 neutralization.