Linking GOLPH3 and Extracellular Vesicles Content—a Potential New Route in Cancer Physiopathology and a Promising Therapeutic Target is in Sight?

Abstract

Golgi phosphoprotein 3 (GOLPH3), a highly conserved phosphatidylinositol 4-phosphate effector, is required for maintenance of Golgi architecture, vesicle trafficking, and Golgi glycosylation. GOLPH3 overexpression has been reported in several human solid cancers, including glioblastoma, breast cancer, colorectal cancer, nonsmall cell lung cancer, epithelial ovarian cancer, prostate cancer, gastric cancer, and hepatocellular carcinoma. Although the molecular mechanisms that link GOLPH3 to tumorigenesis require further investigation, it is likely that GOLPH3 may act by controlling the intracellular movement of key oncogenic molecules, between the Golgi compartments and/or between the Golgi and the endoplasmic reticulum. Indeed, numerous evidence indicates that deregulation of intracellular vesicle trafficking contributes to several aspects of cancer phenotypes. However, a direct and clear link between extracellular vesicle movements and GOLPH3 is still missing. In the past years several lines of evidence have implicated GOLPH3 in the regulation of extracellular vesicle content. Specifically, a new role for GOLPH3 has emerged in controlling the internalization of exosomes containing either oncogenic proteins or noncoding RNAs, especially micro-RNA. Although far from being elucidated, growing evidence indicates that GOLPH3 does not increase quantitatively the excretion of exosomes, but rather regulates the exosome content. In particular, recent data support a role for GOLPH3 for loading specific oncogenic molecules into the exosomes, driving both tumor malignancy and metastasis formation. Additionally, the older literature indirectly implicates GOLPH3 in cancerogenesis through its function in controlling hepatitis C virus secretion, which in turn is linked to hepatocellular carcinoma formation. Thus, GOLPH3 might promote tumorigenesis in unexpected ways, involving both direct and indirect routes. If these data are further confirmed, the spectrum of action of GOLPH3 in tumor formation will significantly expand, indicating this protein as a strong candidate for targeted cancer therapy.

Upregulation of GOLPH3 mediated by Bisphenol a promotes colorectal cancer proliferation and migration: evidence based on integrated analysis

“…GOLPH3 is believed to promote cancer cell growth, inhibit cell death, and enhance migration through the regulation of signaling pathways like AKT/mTOR (Yu et al, 2020). These findings position GOLPH3 as a promising target for cancer therapy, offering novel avenues for treatment (Giansanti and Piergentili, 2022). Our study contributes to a comprehensive understanding of GOLPH3's role in colon cancer, particularly its network of effects.…”

“…observed that BPA exposure in mice models altered the immune microenvironment of breast cancer and promoted lung metastasis. GOLPH3, a recently discovered molecule, has emerged as a player in cancer progression (Giansanti and Piergentili, 2022). Multiple studies have reported the upregulation of GOLPH3 in various cancers, strongly associating it with tumor advancement, metastasis, and patient prognosis (Kuna and Field, 2019;Song et al, 2021).…”

“…These effects of GOLPH3 on drug response may be mediated through its influence on Golgi apparatus composition and trafficking functions, which can affect the cellular uptake and distribution of chemotherapeutic drugs (Kuna and Field, 2019). Moreover, GOLPH3 may impact drug resistance mechanisms by altering vesicular trafficking of drug efflux pumps, regulating apoptosis which is a target of many chemotherapeutic agents, and modifying cellular responses to oxidative stress induced by chemotherapy (Li et al, 2014;Hong et al, 2020;Giansanti and Piergentili, 2022). These insights provide a crucial understanding of how GOLPH3 could be targeted or considered in therapeutic strategies.…”

“…Current evidence suggests that the GOLPH3 gene encodes a protein with a pivotal role in the Golgi apparatus, contributing to vesicular trafficking and phosphatidylinositol 4-phosphate signaling (Kuna and Field, 2019). It has become a research hotspot given its oncogenic potential, as it is often overexpressed in various cancers, leading to enhanced tumor growth, progression, and poor prognosis (Giansanti and Piergentili, 2022). Specifically, in colon cancer, GOLPH3 overexpression has been linked to tumor aggressiveness, metastasis, and resistance to therapy.…”