Given that the Golgi is implicated in cell migration and polarity, it is not surprising to find that the Golgi is also important for tumorigenesis or for metastatic dissemination of tumor cells.
Indeed, the structure of the Golgi is altered in many cancers 111, 112 and some Golgi resident proteins have been implicated in controlling tumor formation. Surprisingly, however, none of these proteins is implicated in tumorigenesis because of a function in cell migration and polarity. The first Golgi protein to be linked with cancer was GOLPH3 75. GOLPH3 is a component of the TGN that regulates retrograde transport of proteins from endosomes to the TGN. GOLPH3 is often amplified in different tumors. In vitro, GOLPH3 knockdown reduces anchorage independent growth and proliferation, while its overexpression enhances these processes as well as H-Ras driven transformation. GOLPH3 interacts with VPS35, a protein of
Introduction – Secretory Pathway - 72
the retromer 113. VPS35 was shown to regulate mTOR activity in yeast 114 and accordingly, GOLPH3 overexpression resulted in increased mTOR activity, as assessed by phosphorylation levels of Akt (downstream of mTORC2) and S6K (downstream of mTORC1). Cells overexpressing GOLPH3 gave rise to bigger tumors in mouse xenotransplants. Finally, tumors overexpressing GOLPH3 resulted to be more sensitive to the mTOR inhibitor Rapamycin 75. The study by Scott et al. provided for the first time a mechanistic insight by which a Golgi protein can regulate tumor progression. However, more work is necessary to fully understand the role of GOLPH3 in cancer.
GM130 has ben also linked to cancer. Reduction of GM130 levels by aerosol delivery of shRNA resulted in reduction of tumor growth in the mouse lung 115. The study hints that GM130 loss leads to increased levels of autophagy and reduced proliferation. Even if the proposed mechanism is not completely clear, the finding that a Golgi resident protein is important in cancer is interesting and further studies will be necessary to understand the link between Golgi and cancer.
Figure 1 – Schematic of some of the signaling routes to and from the secretory pathway described in this introduction.
Introduction – Secretory Pathway - 73
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