Ovarian carcinoma cells with low levels of β-F1-ATPase are sensitive to combined platinum and 2-deoxy-d-glucose treatment

Abstract

We have here examined chemopotentiating effects of glycolysis inhibitor 2-deoxy-D-glucose (DG) in two epithelial ovarian carcinoma (EOC) cell lines and 17 freshly isolated ascitic EOC cell samples, and we identify low expression of the β-F1-ATPase involved in mitochondrial ATP production as a candidate marker for sensitivity to this strategy. Although in the majority of samples, DG per se did not induce apoptosis, cotreatment with DG potentiated apoptosis and total antiproliferative effects of cisplatin and, to a lesser degree, carboplatin. In the cell lines, combination treatment with DG and cisplatin or carboplatin at noninhibitory concentrations prevented posttreatment regrowth in drug-free medium over a total of 5 days. DG per se allowed complete recuperation in drug-free medium. The more platinum-resistant a cell line was, the more sensitive it was to potentiation by DG and showed higher glucose uptake, DG-sensitive lactate production, and lower β-F1-ATPase levels. In the ascitic samples, DG reduced the median IC 50 for cisplatin by 68% and, in the most sensitive samples, up to 90%, and DG-mediated potentiation correlated with low expression of β-F1-ATPase. By contrast, cisplatin sensitivity did not correlate with β-F1-ATPase levels. The findings validate targeting cancer cell glucose metabolism for potentiating platinum chemotherapy in EOC and indicate that reduced β-F1-ATPase/oxidative phosphorylation distinguishes cells that are amenable to this strategy.

Repeated cisplatin treatment can lead to a multiresistant tumor cell population with stem cell features and sensitivity to 3-bromopyruvate

“…We have here and earlier observed that SKOV-3/SKOV-3-R cells are highly dependent on glutamine but not on glucose, and are not sensitive to 2-DG; furthermore, that unlike 3-BP, 2-DG does not greatly potentiate cisplatin 27 (and not shown). Here, both SKOV-3 and SKOV-3-R proliferated well in galactose medium in the absence of glucose, but when cisplatin was added to the galactose medium, SKOV-3-R were more sensitive than SKOV-3 cells.…”

“…The halfmaximal inhibitory concentrations (IC 50 ) over 72 h and regrowth capacity (48 h drug treatment followed by another 72 h in drugfree medium) were assessed based on total cellular protein in the samples, in turn assessed using the Sulforhodamine B assay (Sigma-Aldrich) according to manufacturer's instructions. For details, see Hernlund 27 and Björklund.…”

Up-regulation of the ATPase Inhibitory Factor 1 (IF1) of the Mitochondrial H+-ATP Synthase in Human Tumors Mediates the Metabolic Shift of Cancer Cells to a Warburg Phenotype

“…During ischemia, the ATP hydrolytic activity of the enzyme is inhibited by the ATPase inhibitory factor 1 (IF1 In oxidative phosphorylation, ATP is synthesized by the mitochondrial ATP synthase, a H ϩ -driven rotatory engine of the inner membrane that utilizes as driving force for ATP synthesis the H ϩ electrochemical gradient generated by the respiratory chain (1-4). The cellular expression level of ␤-F1-ATPase, 2 which is the catalytic subunit of the H ϩ -ATP synthase, is diminished in diverse human pathologies (5), which include cancer (6 -9), affording a relevant marker of disease progression (6, 7, 10 -12) and of the response to chemotherapy (7,(13)(14)(15). Moreover, the down-regulation of ␤-F1-ATPase in lung carcinomas (12) and colon cancer cells (15) also provides a mechanistic explanation to the increased glucose avidity of carcinomas, i.e.…”

“…The cellular expression level of ␤-F1-ATPase, 2 which is the catalytic subunit of the H ϩ -ATP synthase, is diminished in diverse human pathologies (5), which include cancer (6 -9), affording a relevant marker of disease progression (6, 7, 10 -12) and of the response to chemotherapy (7,(13)(14)(15). Moreover, the down-regulation of ␤-F1-ATPase in lung carcinomas (12) and colon cancer cells (15) also provides a mechanistic explanation to the increased glucose avidity of carcinomas, i.e.…”

Pathway-gene identification for pancreatic cancer survival via doubly regularized Cox regression

“…In our previous work [16], we applied a lasso penalized Cox regression method, for the first time, to investigate the signature genes that are correlated to the pancreatic cancer survival time. We identified 12 genes associated with the pancreatic cancer survival and eight of them have been confirmed to be genetically altered and differentially expressed in the cancer of gastric, colorectal, ovarian, breast, skin, kidney, colon, lung, and pancreatic in in vivo and in vitro experiments [17-25]. It has been shown that these survival-associated genes can also help to grade the stage and estimate the survival time of the PDAC patients.…”