Abnormal glycosylation and altered Golgi structure in colorectal cancer: dependence on intra‐Golgi pH

Abstract

Abnormal glycosylation of cellular glycoconjugates is a common phenotypic change in many human tumors. Here, we explore the possibility that an altered Golgi pH may also be responsible for these cancer-associated glycosylation abnormalities. We show that a mere dissipation of the acidic Golgi pH results both in increased expression of some cancer-associated carbohydrate antigens and in structural disorganization of the Golgi apparatus in otherwise normally glycosylating cells. pH dependence of these alterations was confirmed by showing that an acidification-defective breast cancer cell line (MCF-7) also displayed a fragmented Golgi apparatus, whereas the Golgi apparatus was structurally normal in its acidification-competent subline (MCF-7/AdrR). Acidification competence was also found to rescue normal glycosylation potential in MCF-7/AdrR cells. Finally, we show that abnormal glycosylation is also accompanied by similar structural disorganization and fragmentation of the Golgi apparatus in colorectal cancer cells in vitro and in vivo. These results suggest that an inappropriate Golgi pH may indeed be responsible for the abnormal Golgi structure and lowered glycosylation potential of the Golgi apparatus in malignant cells. ß

Actin filaments are involved in the maintenance of Golgi cisternae morphology and intra‐Golgi pH

“…Actin depolymerization may impair this functional coupling and generate an inappropriate gradient formation (and intra-Golgi pH), which at ultrastructural level would initially lead to cisternae swelling and then to their collapse. Abnormal ion gradients and pH coupled to the loss of actin cytoskeleton integrity in the Golgi complex could impair both protein transport-and non-transport-associated functions (for instance, protein and lipid glycosylation) [Axelsson et al, 2001;Kellokumpu et al, 2002]. In line with this hypothesis, interference with either the activity of (V)H þ -ATPase [Yilla et al, 1993] or with actin polymerization [Hirschberg et al, 1998;Jacob et al, 2003;Cobbold et al, 2004] results in an altered post-Golgi transport.…”

JNK2 controls fragmentation of the Golgi complex and the G2/M transition through phosphorylation of GRASP65

“…Thus, we examined the effect of JNK inhibition in MCF7 cells, which is a tumour cell line known to have a fragmented Golgi (Kellokumpu et al, 2002) and that requires JNK signalling for its proliferation (Mingo-Sion et al, 2004), as confirmed by their higher JNK activity compared to HeLa cells (supplementary material Fig. S2A).…”

Src kinase regulates the integrity and function of the Golgi apparatus via activation of dynamin 2

“…A variety of tumor cell types exhibit Golgi complexes that are fragmented and dispersed by an unknown mechanism (16). Cultured cells from different human pancreatic epithelial tumor cell lines (HPAF-II, BxPC-3) were stained for a Golgi marker that was detected by immunofluorescence.…”