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Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Prostate cancer progresses to lethal metastatic castration-resistant prostate cancer (mCRPC) driven by αv integrins.
  • This progression is linked to Golgi disorganization and activation of the ATF6 branch of the unfolded protein response (UPR).
  • Altered glycosylation, specifically N-acetylglucosaminyltransferase-V (MGAT5)-mediated, and Galectin-3 (Gal-3) clustering are implicated in integrin overexpression, but the underlying mechanism is unclear.

Purpose of the Study:

  • To elucidate the mechanism linking Golgi disorganization, UPR activation, and altered glycosylation in prostate cancer progression.
  • To investigate the role of MGAT5, MGAT3, and Gal-3 in integrin αv localization and function.
  • To evaluate the therapeutic potential of targeting ATF6 and autophagy in mCRPC.

Main Methods:

  • HALO analysis of immunohistochemistry (IHC) on primary and mCRPC samples.
  • Ethanol-induced endoplasmic reticulum (ER) stress model in prostate cancer cell lines (PC-3, DU145).
  • Assessment of Golgi morphology, protein localization (MGAT3, Gal-3), and integrin αv expression.
  • Inhibition of ATF6 and autophagy (using hydroxychloroquine - HCQ) in cell lines and orthotopic tumor models.

Main Results:

  • A strong association between integrin αv and Gal-3 at the plasma membrane (PM) was observed in prostate cancer samples.
  • Golgi fragmentation and MGAT3 mislocalization to the ER were identified as causes of MGAT5 activation.
  • Ethanol exposure exacerbated Golgi scattering, activated MGAT5, and increased PM integrin expression, linking alcohol consumption to prostate cancer mortality.
  • ATF6 depletion reduced Golgi fragments and UPR.
  • Autophagy inhibition (HCQ) restored Golgi structure, rescued MGAT3 localization, blocked MGAT5 activity, and reduced cell surface Gal-3.
  • Loss of Gal-3 decreased PM integrins and increased their internalization.
  • Combined ATF6 depletion and HCQ treatment synergistically reduced integrin αv and Gal-3, suppressed tumor growth, and decreased metastasis.

Conclusions:

  • Golgi fragmentation and MGAT3 mislocalization drive MGAT5-mediated glycosylation and integrin overexpression in mCRPC.
  • Alcohol consumption exacerbates these changes, contributing to prostate cancer mortality.
  • Combined inhibition of ATF6 and autophagy presents a promising therapeutic strategy for mCRPC by reducing integrin signaling and tumor progression.