Onco-Golgi and Er Stress: The Drivers of Prostate Cancer Progression

​In the United States, prostate cancer (PCa) is the second-leading cause of cancer death in men. Multiple observations indicate the link between prostate carcinogenesis, stress of endoplasmic reticulum (ER stress), and impairment of Golgi morphology. We reported that PCa cells employ a self-activation mechanism of ATF6-mediated ER stress caused by Golgi disorganization and associated with enhanced androgen receptor transactivation. However, the role of ER stress and Golgi fragmentation in the development of castration-resistant prostate cancer (CRPC) is still unknown. CRPC is characterized by the enhanced activity and expression of integrins. Different classes of integrins, mostly alphav beta3, alphav beta5, and alphav beta6, form abnormal integrin repertoire at the plasma membrane (PM) due to the high affinity of their glycans (N-acetyllactosamine, LacNAc) to Galectin-3. This, however, is possible only when integrins are specifically glycosylated in Golgi by glycosyltransferases, MGAT5 or GalT/B3GN, which activation relies on the structural reorganization of Golgi matrix proteins golgins. In addition, underglycosylated integrins, carrying high mannose glycans, can also enhance prostate tumor cells' migratory and invasive capabilities. Here, we provide data indicating that: (a) Golgi disorganization in advanced PCa cells associates with the atypical activity of MGAT1 glycosyltransferase in Golgi, which is caused monomerization of the largest golgin giantin; (b) severity of PCa correlates with expression of MGAT5- and GalT/B3GNT-modified integrins; (c) appearance of high-mannose integrins at the cell surface is likely mediated by ER-PM junctions and triggered by ATF6-mediated ER stress; (d) treatment of advanced PCa cells with anti-malarial drug hydroxychloroquine (HCQ) restores compact Golgi, thus blocking the activity of MGAT5 and GalT/B3GNT enzymes. Our central hypothesis is that ER stress, Golgi disorganization, and remodeling of Golgi matrix proteins impair N-glycosylation of integrins, which results in their enhanced representation at the cell surface and more aggressive phenotype of PCa cells.

Learning Objectives:

1. Elucidate the mechanism of abnormal glycosylation of integrins by studying the impact of Golgi disorganization on differential distribution of golgins and N-glycosylation enzymes. 

2. Examine the effects of ATF6-mediated ER stress on the expression and trafficking of integrins to the cell surface. 

3. Discuss the outcome of ATF6 depletion/inhibition combined with hydroxychloroquine treatment on the progression of a prostate tumor.