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Biomedical subjects

Ilmo Kellokumpu

Publications and source records attributed to Ilmo Kellokumpu.

6 recordsLinked to original sources
PubMed2006

Elevated Golgi pH in breast and colorectal cancer cells correlates with the expression of oncofetal carbohydrate T-antigen.

Altered glycosylation has turned out to be a universal feature of cancer cells, and in many cases, to correlate with altered expression or localization of relevant glycosyltransferases. However, no such correlation exists between observed enzymatic changes and the expression of the oncofetal Thomsen-Friedenreich (T)-antigen, a core 1 (Gal-beta1 --> 3-GalNAc-ser/thr) carbohydrate structure. Here we report that T-antigen expression, instead, correlates with elevated Golgi pH in cancer cells. Firstly, using a Golgi-targeted green fluorescent protein (GT-EGFP) as a probe, we show that the medial/trans-Golgi pH (pHG) in a high proportion of breast (MCF-7) and colorectal (HT-29, SW-48) cancer cells is significantly more alkaline (pHG > or = 6.75) than that of control cells (pHG 5.9-6.5). The pH gradient between the cytoplasm and the Golgi lumen is also markedly reduced in MCF-7 cells, suggesting a Golgi acidification defect. Secondly, we show that T-antigen expression is highly sensitive to changes in Golgi pH, as only a 0.2 pH unit increase was sufficient to increase T-antigen expression in control cells. Thirdly, we found that T-antigen expressing MCF-7 cells have 0.3 pH units more alkaline Golgi pH than non-expressing MCF-7 cells. Fourthly, in all cell types examined, we observed significant correlation between the number of T-antigen expressing cells and cells with a markedly elevated Golgi pH (pHG > or = 6.75). Consistent with these observations in cultured cells, cells in solid tumors also heterogenously expressed the T-antigen. Thus, elevated Golgi pH appears to be directly linked to T-antigen expression in cancer cells, but it may also act as a more general factor for altered glycosylation in cancer by affecting the distribution of Golgi-localized glycosyltransferases.

Antigens, Neoplasm↗
PubMed2004

Defective acidification of intracellular organelles results in aberrant secretion of cathepsin D in cancer cells.

Aberrant secretion of lysosomal hydrolases such as (pro)cathepsin D (proCD) is a common phenotypic change in many human cancers. Here we explore the underlying molecular defect(s) and find that MCF-7 breast and CaCo-2 colorectal cancer cells that are unable to acidify their endosomal compartments secreted higher amounts of proCD than did acidification-competent cancer cell types. The latter secreted equivalent amounts of proCD only after dissipation of their organellar pH gradients with NH(4)Cl. Assessing the critical steps that resulted in proCD secretion revealed that the Golgi-associated sorting receptor for CD, i.e. the cation-independent mannose-6-phosphate receptor (MPR300), was aberrantly distributed in acidification-defective MCF-7 cells. It accumulated mainly in late endosomes and/or lysosomes as a complex with its ligand (proCD or intermediate CD), as evidenced by its co-localization with both CD and LAMP-2, a late endosome/lysosome marker. Our immunoprecipitation analyses also showed that MCF-7 cells possessed 7-fold higher levels of receptor-enzyme complexes than did acidification-competent cells. NH(4)Cl induced similar receptor redistribution into LAMP-2-positive structures in acidification-competent cells but not in MCF-7 cells. The receptor also recovered its normal Golgi localization upon drug removal. Based on these observations, we conclude that defective acidification results in the aberrant secretion of proCD in certain cancer cells and interferes mainly with the normal disassembly of the receptor-enzyme complexes and efficient receptor reutilization in the Golgi.

Acids↗
PubMed2003

Day-case stapled (circular) vs. diathermy hemorrhoidectomy: a randomized, controlled trial evaluating surgical and functional outcome.

PURPOSE: Stapled hemorrhoidectomy may be associated with less pain and faster recovery than conventional hemorrhoidectomy for prolapsing hemorrhoids. Therefore, the outcome of stapled hemorrhoidectomy was compared with that of diathermy hemorrhoidectomy in a randomized, controlled trial. METHODS: Sixty patients with third-degree hemorrhoids were randomly assigned to stapled hemorrhoidectomy (n = 30) or to diathermy hemorrhoidectomy in a day-case setting. Visual analog scale was used for postoperative pain scoring. Surgical and functional outcome was assessed at six weeks and one year after surgery. RESULTS: Operation time was a median of 21 (range, 11-59) minutes in the stapled group. 22 (range, 14-40) minutes in the diathermy group. Day-case surgery was successful in 24 patients (80 percent) in the stapled group vs. 29 patients (97 percent) in the diathermy group. Average pain in the stapled group was significantly lower than in the diathermy group (median, 1.8 (0.1-4.8) vs. 4.3 (1.4-6.2), 95 percent confidence interval difference medians, 1.15-3.85, P = 0.0002, Mann-Whitney U test) as was the average pain expected by the patients (median -2.7 (-0.15-0.8) vs. 0.006 (-4.05-0.5) respectively, 95 percent confidence interval difference medians, 0.5-3.55, P = 0.0018, Mann-Whitney U test). Postoperative morbidity and time off work were not significantly different between the diathermy and stapled groups. Seven treatment failures in the stapled group and one in the diathermy group necessitated other treatments at a later date. Patient satisfaction scores in the stapled and diathermy group were similar. Symptoms attributed to difficult rectal evacuation decreased significantly after surgery. CONCLUSIONS: Stapled hemorrhoidectomy is a significantly less painful operation than diathermy hemorrhoidectomy, but does not seem to offer significant advantages in terms of hospital stay or symptom control in the long term. Hemorrhoidectomy may improve symptoms of difficult rectal evacuation.

Adult↗
PubMed2002

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

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.

Animals↗
PubMed2002

[Rectal cancer].

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Combined Modality Therapy↗