|Year : 2018 | Volume
| Issue : 9 | Page : 450-456
Evaluation of the relationship of erythrocyte membrane Na+/K+-ATPase enzyme activity and tumor response to chemoradiotherapy in patients diagnosed with locally advanced nonsmall cell lung cancer and glioblastoma multiforme
Cigdem Damla Cetinkaya1, Mehmet Gurbilek1, Mehmet Koc2
1 Department of Medical Biochemistry, School of Medicine, Necmettin Erbakan University, Konya, Turkey
2 Department of Radiation Oncology, School of Medicine, Necmettin Erbakan University, Konya, Turkey
|Date of Web Publication||29-Jun-2018|
Cigdem Damla Cetinkaya
Department of Medical Biochemistry, School of Medicine, Necmettin Erbakan University, 42080, Konya
Source of Support: None, Conflict of Interest: None
Context: Radiotherapy is the commonly used therapeutic modality for inoperable cancer types. We investigated chemoradiotherapy (CRT) effects on the Na +/K +-ATPase enzyme.
Aims: The aim of the present study was to determine the usefulness of Na +/K +-ATPase enzyme as a prognostic factor and as a potential target for increasing the CRT response of nonsmall cell lung cancer (NSCLC) and glioblastoma multiforme (GBM).
Settings and Design: We prospectively evaluated 30 patients (all were treated with CRT) and 20 healthy controls.
Subjects and Methods: Blood samples were taken before and after the completion of CRT from the patients and once from the control group. Erythrocyte membranes were isolated and Na +/K +-ATPase enzyme activities were measured.
Statistical Analysis Used: The statistical significance was calculated using the one-way analysis of variance test and the Tukey's test.
Results: Na +/K +-ATPase activity levels were increased in the patient groups before completion of CRT CRT, when compared to the control group. A significant decrease in Na +/K +-ATPase activity was noted in the patient groups after the completion of CRT when compared to before CRT, but the activity remained higher than in the control group. No relationship was noted between survival and Na +/K +-ATPase activity in NSCLC and GBM patients.
Conclusion: Levels of Na +/K +-ATPase activity were initially high in patients with NSCLC and GBM, and decreased after the completion of CRT. This supports a linkage between the altered activity of Na +/K +-ATPase and the treatment effects of CRT. The observed change in Na +/K +-ATPase activity in cancer patients receiving CRT suggests that targeting this enzyme could represent a novel mean of combatting NSCLC and GBM.
Keywords: Chemoradiotherapy, erythrocyte membrane, glioblastoma multiforme, Na+/K+-ATPase, nonsmall cell lung cancer
|How to cite this article:|
Cetinkaya CD, Gurbilek M, Koc M. Evaluation of the relationship of erythrocyte membrane Na+/K+-ATPase enzyme activity and tumor response to chemoradiotherapy in patients diagnosed with locally advanced nonsmall cell lung cancer and glioblastoma multiforme. J Can Res Ther 2018;14, Suppl S2:450-6
|How to cite this URL:|
Cetinkaya CD, Gurbilek M, Koc M. Evaluation of the relationship of erythrocyte membrane Na+/K+-ATPase enzyme activity and tumor response to chemoradiotherapy in patients diagnosed with locally advanced nonsmall cell lung cancer and glioblastoma multiforme. J Can Res Ther [serial online] 2018 [cited 2020 Jan 28];14:450-6. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/450/229637
| > Introduction|| |
Lung cancer is the most common cause of cancer death worldwide  and can be classified into two major types as follows: small cell lung cancer and nonsmall cell lung cancer (NSCLC). NSCLC accounts for more than 85% of lung cancer cases, and its standard treatment, for patients with good performance status and inoperable Stage III, is combined chemoradiotherapy (CRT). Nevertheless, the overall 5 years survival rate remains as low as 15% for NSCLC, despite surgical intervention and the use of newer adjuvant chemotherapy (CT) drugs. Identification of new markers would, therefore, be useful for early diagnosis, determining prognosis, and aiding the selection of appropriate treatments.
Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor in adults. The classified name for GBM, according to the World Health Organization, is “glioblastoma,” but it is also known as Grade IV Astrocytoma. GBM patients have an approximate survival expectancy of only 14 months despite the current standard treatment: surgical resection to the extent feasible, followed by adjuvant radiotherapy (RT), plus temozolomide given concomitantly with and after RT.
RT is the commonly used therapeutic modality for inoperable cancer types. The effects of RT are mediated by the production of free radicals, which induce lipid peroxidation that leads to structural and functional damage to cellular membranes. Membranes are vital for biological systems, and their integrity is essential for normal cell functions. Oxidative damage to the lipid membranes may cause the uncoupling of membrane-bound ATPases, thus reducing their activity and disrupting cellular homeostasis.
Na +/K +-ATPase is an enzyme located in the plasma membrane. The Na +/K +-ATPase enzyme pumps sodium out of cells, while pumping potassium into cells. It has antiporter-like activity, but is not actually an antiporter since both molecules move against their concentration gradients. The active form of Na +/K +-ATPase consists of primarily two noncovalently attached subunits as follows: A 110 kDa catalyticα-subunit and a 45–55 kDa glycosylated β-subunit. Several reports have noted changed expression in Na +/K +-ATPase subunits in a number of cancer tissues derived from kidney, bladder, breast, colon, and pancreas.
Na +/K +-ATPase, a membrane-bound sulfhydryl-containing integral membrane protein, maintains resting cell membrane potential by pumping sodium and potassium ions against the concentration gradient across the cell membrane. Na +/K +-ATPase is known to be highly susceptible to oxidative stress.
In this study, we investigated the effects of CRT on erythrocyte membrane Na +/K +-ATPase enzyme activity in patients diagnosed with NSCLC and GBM. The aim was to evaluate the usefulness of Na +/K +-ATPase enzyme as a potential target for increasing the CRT response of tumors and to assess this enzyme activity as a prognostic factor.
We, therefore, attempted to investigate the effects of applied cancer treatment regimens on erythrocyte membrane Na +/K +-ATPase enzyme activity which has an important role in the physiopathology of NSCLC and GBM. In addition, sodium pump activity could be used to determine new therapeutic strategies in these cancers.
| > Subjects and Methods|| |
Study design and ethical guidelines
The patients in this study were selected from those admitted to the Department of Radiation Oncology, Meram Medical School, Necmettin Erbakan University. All participants provided written informed consent. Approval for this study was obtained from the Meram Medical Faculty Ethics Committee, Necmettin Erbakan University on 21.09.2012 in decision no: 2012/222.
Selection of cases and controls
NSCLC patients were inoperable Stage III, and GBM patients had postoperative with or without residual tumors. Neither group of patients had previously undergone CT or RT. All participants provided written informed consent. Heparinized blood samples were taken from 20 NSCLC patients, 10 GBM patients, and 20 healthy volunteers for data measurements. Samples were taken before and after 6 weeks of RT and CT (temozolomide oral tuberculosis 75 mg/m 2/day for GBM and paclitaxel 40–50 mg/m 2/week, with carboplatin area under the curve 2/week or cisplatinum 75 mg/m 2 with etoposide 100 mg/m 2 intravenous infusion for NSCLC) from the patients and once from the control group. Chemotherapeutics were used for radiosensitization not for curative treatment. Control group did not receive CRT during the study.
Inclusion and exclusion criteria
The inclusion criteria were included as follows: (1) histologically confirmed GBM and Stage III cases of NSCLC, (2) patients in the age group of 40–70 years with a Karnofsky Performance Status score ≥70, and (3) patients belonging to similar ethnicity. Exclusion criteria were included as follows: (1) patients who previously received CT or RT, (2) patients with a secondary malignancy, (3) patients with a history of any drug addiction, chronic smoking habit, or alcohol addiction, (4) patients with any metabolic or endocrine disorders, and (5) patients with any chronic inflammatory condition.
Isolation of red blood cell membranes
Erythrocyte membranes were isolated according to the procedure of Dodge et al. with modifications in the buffer composition. A volume of 10 ml fresh human blood was collected with heparin as an anticoagulant, before CRT, and after 6 weeks CRT. Plasma was separated by centrifugation at 1000 g for 4 min. Excess plasma and platelets were removed, the erythrocytes were washed three times with Tris-NaCl buffer (5 mM Tris, pH 7.4 + 156 mM NaCl), and the supernatant red fluid was decanted. A suspension of isolated erythrocyte membranes (ghosts) was prepared by hemolysis of approximately 2 ml of erythrocytes in 11.3 ml of ice cold 10 mM Tris-HCl buffer (pH 7.4), followed by incubation at 0°C –4°C for 15 min. Approximately 6 ml of hemolysate was added to the same amount of buffer (10 mM Tris–HCl, pH 7.4), followed by centrifugation at 20,000 g for 30 min at 9°C –10°C; this process was repeated three times. Colorless or pale pink ghosts were stored at −80°C until further analysis.
Assay of Na +/K +-ATPase
The total ATPase activity was assayed using a modification of the method of Kitao and Hattori. In brief, 200 μl of ghost suspension was incubated with 800 μl of reaction medium (100 mM NaCl, 5 mM KCl, 6 mM MgCl2, 0.1 mM EDTA, and 3 mM Na2 ATP) at 37°C for 10 min. The reaction was stopped by addition of 50 μl of 10% sodium dodecyl sulfate and mixed by inversion. If turbidity was present, the mixture was centrifuged at 5,500 g for 10 min, and the supernatant was used for measurements. Samples were analyzed with Abbott kits (Abbott Laboratories, Chicago, IL, USA) manufactured for use with the Architect c16000 auto-analyzer. Microprotein was measured spectrophotometrically, and phosphorus levels were measured using the phosphomolybdate method. The results were expressed as μmol of Pi per milligrams of membrane protein (μmol Pi mg prt −1 10dk −1).
Statistical analysis was performed using SPSS software version 21.0 (IBM-SPSS, Chicago, USA). The statistical significance was calculated using the one-way analysis of variance test and the Tukey's test for post hoc analysis. NSCLC and GBM survival rates were examined using the Tarone–Ware test. Correlation between survival rate and Na +/K +-ATPase activity was evaluated using LR Cox regression analysis. The relationship between survival and hemogram parameters was also investigated (hemoglobin [Hb], red cell distribution width, white blood cell, erythrocyte count [RBC], platelets, neutrophils, eosinophils, lymphocytes, and monocytes levels were obtained retrospectively). The value of P < 0.05 was considered statistically significant.
| > Results|| |
Patients diagnosed with NSCLC and GBM showed a significant elevation of Na +/K +-ATPase activity before treatment (3.61 ± 0.48 and 3.56 ± 0.44, respectively) when compared to the healthy control group (2.54 ± 0.23, P < 0.0001). However, no significant difference was noted for Na +/K +-ATPase activity between NSCLC and GBM patients before CRT (P = 0.986) [Table 1] and [Figure 1].
|Table 1: Levels of erythrocyte membrane Na+/K+-ATPase enzyme activity in control and patient groups|
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|Figure 1: Activities of Na+/K+-ATPase (μmol Pi mg prt−1 10dk−1) in nonsmall cell lung cancer and glioblastoma multiforme, and healthy control groups|
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Na +/K +-ATPase enzyme activity decreased after CRT but was still significantly higher after completion of CRT in patients with GBM than in the control group (3.08 ± 0.41 and 2.54 ± 0.23, respectively, P = 0.005). In addition, significantly higher levels were evident in the NSCLC group when compared to control group (3.12 ± 0.47 and 2.54 ± 0.23, respectively, P < 0.0001). Na +/K +-ATPase activity was not significantly different between the NSCLC and GBM groups after the completion of CRT (P = 0.815) [Table 1].
Na +/K +-ATPase activity in patients with NSCLC was significantly lower after the completion of CRT than before treatment (3.12 ± 0.47 and 3.61 ± 0.48, respectively, P = 0.002). Similarly, Na +/K +-ATPase activities in patients with GBM were significantly lower after treatment than before CRT (3.08 ± 0.41 and 3.56 ± 0.44, respectively, P = 0.014) [Table 1] and [Figure 1].
Survival rates (Mean ± standard deviation [median]) in patients with NSCLC and GBM were 274.22 ± 188.5 (290.5) and 466.7 ± 377.4 (303), respectively [Table 2]. The LR Cox regression analysis revealed that Na +/K +-ATPase enzyme activity was not associated with survival of patients [Table 2]. The pre-CRT median Hb levels were 12.5 g/dL in NSCLC and 13.2 g/dL in GBM; Hb was the only hemogram parameter associated with survival. Low levels of pre-CRT Hb were associated with worse outcome of NSCLC patients (hazard ratio = 0.508, P = 0.031, 95% confidence interval: 0.274–0.941) [Figure 2]. No differences were evident between NSCLC and GBM survival curves as determined by the Tarone–Ware test (P = 0.207) [Figure 3].
|Figure 2: Scatter plot graphs showing the correlation between survival and hemoglobin (g/dL) levels in patients with nonsmall cell lung cancer and glioblastoma multiforme|
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|Figure 3: Survival of patients with glioblastoma multiforme and nonsmall cell lung cancer|
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| > Discussion|| |
An urgent need exists for new biological targets for NSCLC and GBM treatment due to the low overall survival rates for these diseases. The present study revealed that erythrocyte membrane Na +/K +-ATPase enzyme activity is increased in patients with NSCLC and GBM before CRT.
To the best of our knowledge, this is the first study that showed the effects of CRT on erythrocyte membrane Na +/K +-ATPase enzyme activity. The present study revealed that increased activity of the Na +/K +-ATPase enzyme before CRT and a decreased activity after CRT in NSCLC and GBM patients. Despite the decline after CRT, the remaining Na +/K +-ATPase activity was still significantly higher after the completion of CRT in both cancer patient groups.
The erythrocyte membrane Na +/K +-ATPase is a heterodimeric transmembrane protein that regulates ion homeostasis and acts as a signal transducer for the regulation of many cellular mechanisms, including those involved in tumor cell growth. This protein helps to regulate the electrochemical gradient across the plasma membrane and allows the establishment of the resting potential across the membrane, which is vital for the occurrence of other reactions across the plasma membrane. The Na +/K +-ATPase has recently been found to play a role in cancer initiation, growth, development, and metastasis through its regulation of various cell survival and death pathways. In our study, Na +/K +-ATPase activity levels both before and after CRT were higher in patients with NSCLC and GBM than in the control group.
Certain fluctuations in Na +/K +-ATPase pump activity and mutations of the protein can result in increased growth in cancer cells. The cellular processes and pathways that exhibit these effects include the epithelial to mesenchymal transition, p21 Cip, p38 mitogen-activated protein kinase cascade, phosphoinositide 3-kinase/protein kinase B/the mammalian target of rapamycin pathway, and cholesterol homeostasis. These various cellular mechanisms were probably influenced by the increased activity of Na +/K +-ATPase observed in our cancer patients.
Some studies have showed that Ionizing radiation is one of the important exogenous sources of DNA damage, cell membrane dysfunction, and oxidative stress. Increased oxidative stress causes cellular ATP depletion due to mitochondrial dysfunction. Cellular ATP loss and nonenzymatic glycation result in impaired function of Na +/K +-ATPase. RT has a key role in the treatment of NSCLC and GBM, and the free radicals created by RT are potential inhibitors of the Na +/K +-ATPase activity. Free radicals cause lipid peroxidation, which could be responsible for alterations in Na +/K +-ATPase activity. Ozmen and Askın's study showed decreased Na +/K +-ATPase activity during treatment in breast cancer have been linked to the RT. In agreement with these previous results, we found that the activity of Na +/K +-ATPase was reduced in our cancer patients after CRT.
The cancer-promoting effect of these pathways is correlated with the differentiating expressions of theα-and β-subunits of the Na +/K +-ATPase. Numerous studies have reported changes in Na +/K +-ATPase in the course of malignant transformation, with evidence that these occur at the very early stages of tumorigenesis. These changes can include altered Na +/K +-ATPase density at the plasma membrane of tumor cells, as well as differences in isozyme expression. Indeed, β1 is very frequently downregulated in human epithelial cancer cells,, whereasα-subunits seem to be upregulated in certain malignant cells.
As a novel target, The Na +/K +-ATPase α1 subunit shows markedly higher activity in a significant proportion of NSCLC clinical samples when compared to normal lung tissue. Studies have also indicated an apparent upregulation of NaK α1 subunits in a proportion of glioblastomas but not in normal brain tissues. For example, Lefranc and Kiss  investigated the involvement of Na +/K +-ATPase in the migration and proliferation of glioma cells and suggested that glioblastoma patients who do not respond to CT and whose tumors over-express NaK α1 subunits could benefit from a treatment using ligands with marked binding affinity for the NaK. α1 subunit.
We observed that high Na +/K +-ATPase enzyme activity levels in NSCLC and GBM patients were decreased after 6 weeks of RT but remained significantly higher than in the control group. Possibly, the degree of inhibition of this enzyme was inadequate in the GBM and NSCLC patients after CRT. Therefore, the use of agents in addition to CRT would be necessary to reduce Na +/K +-ATPase activity to the levels seen in the control group.
Due to its role in fundamental cellular functions, Na +/K +-ATPase has been considered as a target for drugs. Tocotrienol, a vitamin E analog, was associated with reduced oxidative stress. Abdul Nasır et al. have shown that Tocotrienol associated restoration of ATPase functions involves reduction of lens oxidative stress besides correction of lens ATP levels. In addition, vitamin E and tocotrienol have also been shown to normalize the oxidative damage-induced reduction in Na +/K +-ATPase activity in the carbofuran-treated rat.
Cardiac glycosides such as ouabain, digoxin, and digitoxin are used as therapeutic agents for the treatment of heart failure and cardiac arrhythmias. They have also been shown to exhibit an antiproliferative effect on cancer cells due to their inhibitory effect on the Na +/K +-ATPase. Beneficial effects of digitalis treatment have been suggested by epidemiological studies. The Na +/K +-ATPase has been targeted using specific cardiac glycosides in NSCLC  and GBM  and breast cancer., Kometiani et al. have explored the mechanism of the growth inhibitory effects of these drugs on the breast cancer cell line. They have found that ouabain inhibited the pumping function of Na +/K +-ATPase and had no effect on cell viability, but it inhibited proliferation. The importance of Na +/K +-ATPase in anticancer therapy has also been suggested using the monoterpene perillyl alcohol that acted differently from the classical inhibitor ouabain by interfering in the initial phase of the enzyme's catalytic cycle in a glioblastoma cell line. The study findings support the idea that in addition to CRT, inhibiting the increased levels of Na +/K +-ATPase enzyme activity observed in GBM and NSCLC could represent a novel means of treatment.
We also investigated the relationship between Na +/K +-ATPase enzyme activity and survival in an effort to understand the prognostic importance of the enzyme activity. Na +/K +-ATPase activity was not associated with survival of patients and had no direct effect on survival, but it may have an indirect association due to its effects on numerous cellular mechanisms. The Hb level was significantly associated with survival of patients with NSCLC, and hence, survival of these patients may depend on whether patients are in an anemic state [Table 2] and [Figure 2].
In summary, we have found the increased activity of the erythrocyte membrane Na +/K +-ATPase enzyme before CRT and a decreased activity after CRT in NSCLC and GBM patients. Despite the decline after CRT, the remaining Na +/K +- ATPase activity was still significantly higher after the completion of CRT in both cancer patient groups. We have found that erythrocyte membrane Na +/K +-ATPase enzyme activity increased in patients with NSCLC and GBM before CRT and decreased after the completion of CRT. The study results indicate that decreased activity of Na +/K +-ATPase is linked to the treatment effects of CRT. Further studies are required to understand the role of Na +/K +-ATPase activity and its alterations in response to CRT.
The authors are grateful to Necmettin Erbakan University, Konya, Turkey, for the financial support.
Financial support and sponsorship
This project was supported by a grant from the Scientific and Research Council of Necmettin Erbakan University, project number 121518002.
Conflicts of interest
The authors declare no conflict of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]