Abstract
Golgi phosphoprotein 3 (GOLPH3) has been implicated in the development of carcinomas in many human tissues, and is currently considered a bona fide oncoprotein. Importantly, several tumor types show overexpression of GOLPH3, which is associated with tumor progress and poor prognosis. However, the underlying molecular mechanisms that connect GOLPH3 function with tumorigenicity are poorly understood. Experimental evidence shows that depletion of GOLPH3 abolishes transformation and proliferation of tumor cells in GOLPH3-overexpressing cell lines. Conversely, GOLPH3 overexpression drives transformation of primary cell lines and enhances mouse xenograft tumor growth in vivo. This evidence suggests that overexpression of GOLPH3 could result in distinct features of GOLPH3 in tumor cells compared to that of non-tumorigenic cells. GOLPH3 is a peripheral membrane protein mostly localized at the trans-Golgi network, and its association with Golgi membranes depends on binding to phosphatidylinositol-4-phosphate. GOLPH3 is also contained in a large cytosolic pool that rapidly exchanges with Golgi-associated pools. GOLPH3 has also been observed associated with vesicles and tubules arising from the Golgi, as well as other cellular compartments, and hence it has been implicated in several membrane trafficking events. Whether these and other features are typical to all different types of cells is unknown. Moreover, it remains undetermined how GOLPH3 acts as an oncoprotein at the Golgi. Therefore, to better understand the roles of GOLPH3 in cancer cells, we sought to compare some of its biochemical and cellular properties in the human breast cancer cell lines MCF7 and MDA-MB-231 with that of the non-tumorigenic breast human cell line MCF 10A. We found unexpected differences that support the notion that in different cancer cells, overexpression of GOLPH3 functions in diverse fashions, which may influence specific tumorigenic phenotypes.
Highlights
Compelling experimental evidence indicates that intracellular membrane trafficking factors play important roles in tumorigenesis [1]
We studied Golgi phosphoprotein 3 (GOLPH3) in the estrogen receptor positive (ER+) MCF7 cells, the estrogen receptor negative (ER-) MDA-MB231 cells, and the non-tumorigenic MCF 10A cells
We found that the total levels of GOLPH3 in MCF7 and MDA-MB-231 cells are around twice as high as they are in MCF 10A cells (Fig 1A, lanes 1, 4 and 7, Fig 1B and S1 Table)
Summary
Compelling experimental evidence indicates that intracellular membrane trafficking factors play important roles in tumorigenesis [1]. In several human cancers it has been found deregulation of several members of the Rab family of GTP binding proteins and their effectors, which are key regulators in the endocytic and secretory pathways [2] One such putative membrane trafficking regulator is the protein Golgi phosphoprotein 3 (GOLPH3). The oncogenicity of GOLPH3 seems to be mediated by a mechanism that involves enhanced signaling through the mammalian target of rapamycin (mTOR), conferring cancer cells hypersensitivity to rapamycin [3]. To date, it remains undetermined how GOLPH3 acts as an oncoprotein at the Golgi [26]. GOLPH3 could be mediating several specific functions in different tumor cells, yet little is known about the precise molecular mechanisms and the contribution of these functions to tumorigenesis
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