# The role for alcohol-induced Golgi disorganization in the progression of prostate cancer

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $343,125

## Abstract

ABSTRACT
 Chronic alcohol abuse and alcoholism are considered risk factors for prostate cancer (PCa) progression, but
the mechanism is unknown. The current project will address an important question raised by clinicians: whether
alcohol abstinence is an important therapeutic intervention in PCa. Previously, we found that: (1) fragmentation of
the Golgi complex correlates with the progression of PCa; (2) ethanol (EtOH) induces Golgi disorganization that is
caused by the impaired dimerization of the largest Golgi matrix protein giantin, which, in turn, alters intra-Golgi
localization of some Golgi proteins. Indeed, we recently observed that in androgen-responsive PCa cells, EtOH-
induced Golgi fragmentation leads to translocation of glycogen synthase kinase β (GSK3β) from the Golgi to the
cytoplasm, followed by the activation of HDAC6-HSP90-AR pathway. Additionally, we reported that non-muscle
myosin IIA (NMIIA) motor protein forces EtOH-induced Golgi disruption. Also, alcohol induces endoplasmic
reticulum (ER) stress and unfolded protein response (UPR), which are the known drivers of PCa advancement;
however, the mechanism of EtOH-induced UPR in cancer remains largely uncovered. Here, we found that in low
passage LNCaP cells, one of the UPR sensor, ATF6, is cleaved in Golgi by S1P and S2P proteases; however,
EtOH treatment alters the Golgi localization of S1P and S2P, trapping them in the ER and facilitating ATF6
transactivation. Further, EtOH induces translocation of the glycosyltransferase MGAT3 from the Golgi to the
cytoplasm followed by its degradation. However, MGAT5, the enzyme that competes with MGAT3 for N-glycan
branching, is still retained in the Golgi. This results in MGAT5-mediated glycosylation of pro-metastatic proteins
(including matriptase and integrins) and their overexpression at the cell surface. Finally, we detected that loss of
NMIIA function prevents alcohol-induced Golgi fragmentation in PCa cells. This, in turn, recovers MGAT3’s intra-
Golgi localization and reduces the expression of integrins. In light of these facts, we propose to test the hypothesis
that alcohol accelerates PCa progression through Golgi fragmentation, which: (a) enhances ER stress response via
induction of ATF6-mediated UPR, and (b) stimulates expression of pro-metastatic proteins over their abnormal
MGAT5-mediated glycosylation. Hence, targeting alcohol-induced Golgi fragmentation is therapeutically important.
The three specific aims of the proposed study are to: 1) elucidate the mechanism of alcohol-induced activation of
ER stress by determining how alcohol metabolites induce translocation of Golgi localized S1P and S2P proteases
to the ER; 2) examine the role of EtOH-induced MGAT5-mediated glycosylation in the progression of PCa; and 3)
examine whether inhibition or knockdown of NMIIA prevents EtOH-induced Golgi fragmentation and attenuates the
aggressive phenotype of PCa cells. The approach will include a variety of in vitro and in vivo experiments u...

## Key facts

- **NIH application ID:** 9988320
- **Project number:** 5R01AA027242-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Armen Petrosyan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,125
- **Award type:** 5
- **Project period:** 2019-08-02 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988320

## Citation

> US National Institutes of Health, RePORTER application 9988320, The role for alcohol-induced Golgi disorganization in the progression of prostate cancer (5R01AA027242-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9988320. Licensed CC0.

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