Role of KATP channel activation on measures of mitochondrial function in cancer cells
Bibliographic record
Abstract
822 The ATP gated, inward rectifying, potassium channel (KATP) has been extensively studied in neuronal cells, cardiac myocytes, and pancreatic beta cells. In cardiac myocytes a mitochondrial localized isoform (mtKATP) is thought to be involved in ischemic preconditioning. This channel also has an important role in oncogenesis and tumor promotion of non-excitable cells by modulating plasma membrane potential, inhibiting apoptotic volume decrease, and altering reactive oxygen species (ROS) production and inner membrane potential of the mitochondria. Non-toxic concentrations of ROS have been shown to promote cell survival. We demonstrate a novel function of the mtKATP channel in cancer physiology. RT-PCR and western-blotting were used to examine expression of specific KATP channel subunits. To determine the expression of the complete mtKATP channel, two measures of mitochondrial function were examined. Changes in the mitochondrial inner membrane potential were measured through flow cytometry by comparing changes in the uptake of the potential sensitive dye tetramethyrhodamine methyl ester (TMRM). ROS production was examined by analysis of the conversion of Dichlorofluorescin diacetate (DCFH-DA) to the fluorescent dichloroflurescin also by flow cytometry. We have shown mRNA and protein expression of the pore forming Kir6.2 subunit in human prostate carcinoma (2008 and C13) and human colorectal carcinoma (HT29) cell lines. The observation that the mtKATP channel blocker 5-Hydroxydecanoate (5-HD) could inhibit proliferation of 2008 and C13 cells is consistent with a physiological role for these channels. To determine the consequences of mtKATP blockade we examined the production of ROS in the presence of 5-HD and the mtKATP channel opener Diazoxide (Dia). We found a slight (2.4 fold) increase in ROS production during 5-HD treatment and a 4.6 fold increase in ROS with Dia treatment in the mouse ovarian carcinoma (MLL) cell line. Initial TMRM results suggest 5-HD is able to slightly dissipate the inner mitochondrial membrane potential in 2008 cells. These results demonstrate that non-excitable tumor derived cell lines express a pore forming subunit of the KATP channel. The ability of 5-HD and Dia to act on mitochondrial function suggest that this subunit is expressed as part of a functional mtKATP channel. The impact of potassium permeation through the mtKATP channel into the mitochondrial matrix is postulated to promote oncogensis and tumor promotion through the manipulation of ROS production and maintenance of ATP levels in response to hypoxia. The mtKATP channel could be a novel target for anti-cancer therapy. (This work was supported by the Canadian Institute for Health Research)
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".