|Year : 2022 | Volume
| Issue : 3 | Page : 151-157
Action of the natural compound gomisin a on Ca2+ movement in human prostate cancer cells
Lyh-Jyh Hao1, Rong-An Lin2, Li-Chai Chen3, Jue-Long Wang4, I-Shu Chen5, Chun-Chi Kuo6, Chiang-Ting Chou7, Jau-Min Chien8, Chung-Ren Jan9
1 Department of Endocrinology and Metabolism, Kaohsiung Veteran General Hospital, Tainan Branch; Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan
2 Department of Pharmacy, Kaohsiung Veterans General Hospital, Tainan Branch; Department of Pharmaceutical Science and Technology, Chung Hwa University of Medical Technology, Tainan, Taiwan
3 Department of Pharmacy, Tajen University, Ping Tung, Taiwan
4 Department of Rehabilitation, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
5 Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
6 Department of Nursing, Tzu Hui Institute of Technology, Pingtung, Taiwan
7 Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Puzi City, Chiayi County, Taiwan
8 Department of Pediatrics, Pingtung Christian Hospital, Pingtung, Taiwan
9 Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
|Date of Submission||28-Jan-2022|
|Date of Decision||12-Apr-2022|
|Date of Acceptance||11-May-2022|
|Date of Web Publication||27-Jun-2022|
Prof. Chung-Ren Jan
No. 386, Dazhong 1st Road, Zuoying Dist, Kaohsiung City 81362
Source of Support: None, Conflict of Interest: None
Gomisin A is a dietary lignan compound isolated from the fruit of Schisandra chinensis and has many pharmacological properties, including hepato-protective, anti-diabetic, and anti-oxidative activities. However, the benefit of gomisin A is still not well understood. The action of gomisin A is diverse. However, the effect of gomisin A on Ca2+ signaling in prostate cancer cells is unknown. Ca2+ is a pivotal second envoy that triggers and regulates cellular processes such as apoptosis, fertilization, energy transduction, secretion, and protein activation. The goal of this study was to explore the action of gomisin A on [Ca2+]i and cytotoxicity in PC3 prostate cancer cells. Gomisin A at 100–200 μM provoked [Ca2+]i raises. 20% of the response was reduced by removing external Ca2+. The Ca2+ influx provoked by gomisin A was suppressed by 20% by store-caused Ca2+ entry suppressors: econazole, SKF96365, nifedipine; also by phorbol 12-myristate 13 acetate and GF109203X. Without external Ca2+, gomisin A-caused [Ca2+]i raises were abolished by thapsigargin. In contrast, gomisin A suppressed the [Ca2+]i raises caused by thapsigargin. U73122 fell short to change gomisin A-caused [Ca2+]i responses. Gomisin A (20–100 μM) elicited cytotoxicity in a dose-associated fashion. Blockade of [Ca2+] elevations with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/acetoxy methyl failed to inhibit cytotoxicity of gomisin A. Collectively, gomisin A evoked [Ca2+]i raises and provoked cytotoxicity in a Ca2+-dissociated fashion in prostate cancer cells.
Keywords: Calcium, gomisin A, PC3, prostate, viability
|How to cite this article:|
Hao LJ, Lin RA, Chen LC, Wang JL, Chen IS, Kuo CC, Chou CT, Chien JM, Jan CR. Action of the natural compound gomisin a on Ca2+ movement in human prostate cancer cells. Chin J Physiol 2022;65:151-7
|How to cite this URL:|
Hao LJ, Lin RA, Chen LC, Wang JL, Chen IS, Kuo CC, Chou CT, Chien JM, Jan CR. Action of the natural compound gomisin a on Ca2+ movement in human prostate cancer cells. Chin J Physiol [serial online] 2022 [cited 2022 Aug 11];65:151-7. Available from: https://www.cjphysiology.org/text.asp?2022/65/3/151/348361
| Introduction|| |
Gomisin A is a dietary lignan compound extracted from the fruit of Schisandra chinensis and has many pharmacological effects such as hepato-protective, anti-diabetic, and anti-oxidative activities. Nevertheless, the clinical benefit of gomisin A is not well understood. It was shown that gomisin A modulated aging progress via mitochondrial biogenesis in human diploid fibroblast cells. Gomisin A was shown to ameliorate metastatic melanoma in metastatic phenotypes. Evidence shows that gomisin A was an isoform-specific probe in liver microsomes, and decreased lipopolysaccharide-induced expression of proteins in macrophages. Similarly, gomisin A was reported to inhibit lipopolysaccharide-induced inflammatory responses in microglia. Hwang et al. demonstrated protective action of gomisin A against CCl4-evoked cytotoxicity. Gomisin A was thought to cause apoptosis in HCT-116 cells. Furthermore, gomisin showed anti-apoptotic and hepatoprotective action on liver failure in mice.
Regarding effect of gomisin A on Ca2+ signaling, it was shown that gomisin A induced Ca2+-dependent activation of eNOS in endothelial cells, and protected rat cortical cells from cytotoxicity by inhibiting glutamate-induced [Ca2+]i rises. No evidence has shown that gomisin A increases [Ca2+]i in any cell type. The effect of gomisin A on prostate physiology is unclear.
In PC3 cells, it has been shown that [Ca2+]i rises and death can be induced by stimulation with chemicals including BayK 8644, resveratrol, and celecoxib. Thus, the main goal of this study was to explore the mechanisms of gomisin A-induced Ca2+ signal.
Ca2+ is a pivotal second messenger in cells that is important for fate of cell. A rise in cytosolic Ca2+ level [Ca2+] triggers and modulates numerous cellular phenomena including growth, death, fertilization, protein regulation, fluid secretion, muscle contraction, etc. Two sources are responsible for a [Ca2+]i rise: Ca2+ entry from extracellular solution and/or Ca2+ release from intracellular depots. Extracelluar Ca2+ may enter cells through different receptors, channels, and pumps. The store-operated Ca2+ entry plays a key role in nonexcitable cells. Ca2+ can also be released from the endoplasmic reticulum through phospholipase C (PLC)-mediated IP3 activation or inhibition of the endoplasmic reticulum Ca2+-ATP pumps. Further, this Ca2+ signal can be modulated by many molecules including protein kinase C. The effect of gomisin A on [Ca2+]i is unclear in prostate cells. As summarized above, because a Ca2+ signal can induce various cellular processes, it is essential to explore the pathways of gomisin A-induced [Ca2+]i rises.
| Materials and Methods|| |
The chemicals used in the culture of cells were acquired from Gibco® (Gaithersburg, MD, USA). Aminopolycarboxylic acid/acetoxy methyl (fura-2/AM) and 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid/acetoxy methyl (BAPTA/AM) were purchased from Molecular Probes® (Eugene, OR, USA). All other compounds were purchased from Sigma-Aldrich® (St. Louis, MO, USA).
Culture of cells
PC3 human prostate cancer cells were purchased from Bioresource Collection and Research Center (Taiwan). Cells were kept in RPMI-1640 solution. The solution had fetal bovine serum (10%) and penicillin (100 U/ml)-streptomycin (100 μg.ml) and were kept at a 37°C incubator with a humidified 5% CO2 atmosphere.
Compounds contained in experimental solutions for [Ca2+]i assays
Ca2+-containing solution had 10 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), and 5 mM glucose, 1 mM MgCl2, 2 mM CaCl2, 140 mM NaCl, 5 mM KCl (pH 7.4). Ca2+-free solution had 0.3 mM ethylene glycol tetraacetic acid (EGTA), 3 mM MgCl2, 10 mM HEPES, 5 mM glucose, 140 mM NaCl, 5 mM KCl (pH 7.4). Gomisin A was dissolved in alcohol as a 0.1 M stock solution. Water, ethanol, or dimethyl sulfoxide was chosen to dissolve other chemicals. The dose of organic solvents in the experimental solutions was <0.1% and did not influence resting [Ca2+]i or viability.
Confluent cells grown on 6 cm dishes were trypsinized to become a suspension in culture solution at a concentration of 106/ml. At this point, trypan blue was chosen to check viability which was larger than 95%. Subsequently, cells were incubated with 2 μM fura-2/AM for 30 min at 25°C in Ca2+-containing solution. Then, cells were rinsed with Ca2+-containing medium twice and suspended into a Ca2+-containing suspension at a concentration of 107/ml. Fura-2 fluorescence was performed at 25°C. The cuvette had 0.5 million cells in 1 ml. Fluorescence was recorded with a Shimadzu RF-5301PC spectrofluorophotometer (Kyoto, Japan) by adding 0.1 ml cell suspension to 0.9 ml Ca2+-containing or Ca2+-free medium, by recording excitation signals at 340 nm and 380 nm and emission signal at 510 nm at 1 s intervals. In the assays, chemicals were administered to the cuvette by pausing data collecting for 3 s to open and close the chamber. To calibrate [Ca2+]i, after completion of the assays, CaCl2 (5 mM) and Triton X-100 (0.1%) were administered to the cell suspension to gain the maximal signal followed with EGTA (10 mM) to gain the minimal signal. After 30 min of fluorescence assays, control assays implicated that cells had 95% viability. [Ca2+]i was computed as depicted previously.
Mn2+ smothering of fura-2 fluorescence was conducted in the presence of Ca2+ and 50 μM MnCl2. The rational was that Mn2+ and Ca2+ enter cells through similar pathways. Once in the cells, Mn2+ smothers fluorescence at all excitation wavelengths including Ca2+-insensitive wavelength of 360 nM. Thus, smothering of fura-2 fluorescence at 360 nm excitation wavelength implicates Ca2+ influx into the cell. MnCl2 was administered to cells in the cuvette 30 s before the fluorescence recording began. Results were collected at excitation signal at 360 nm (Ca2+-insensitive) and emission signal at 510 nm at 1-s intervals as depicted formally.
Cell viability analyses
The rational of cell viability assays is that tetrazolium salts are cleaved to formazan by cytosolic enzymes. A rise in the viable cell count leading to a rise in the activity of mitochondrial dehydrogenases in the cells, which enlarges the quantity of formazan dye formed. The live cell count can be calculated by a scanning multiwell spectrophometer. WST-1 (4-[3-[4-lodophenyl]-2-4 (4-nitrophenyl)-2H-5-tetrazolio-1,3-benzene disulfonate) is applied for determination cell viability. These measurements were conducted abiding by manufacturer's instructions (Roche Molecular Biochemical, Indianapolis, IN, USA). Cells were cultured in 96-well plates at a density of 104 cells per well in culture solution overnight with gomisin A. WST-1 (10 μl pure solution) was administered to cells after gomisin A preincubation, and cells were kept for 30 min in an incubator. The cells were treated with gomisin A overnight. In the assays using BAPTA/AM to bind Ca2+ to suppress cytosolic [Ca2+]i raises, cells were pretreated with 5 μM BAPTA/AM for 1 h before treatment with gomisin A. The cells were rinsed once with Ca2+-containing medium and incubated with gomisin A overnight. The absorbance of cells (A450) was verified using a multiwall plate reader. Optical density was normalized to the absorbance of unstimulated cells in each plate and presented as % of control. The absorbance of cells (A450) was decided using an enzyme-linked immunosorbent assay (ELISA) reader. Optical density was normalized to the absorbance of unstimulated cells in each plate and presented as a % of control.
Results are presented as mean standard deviation of three independent experiments. Multiple comparisons between group means were performed by post hoc analysis using the Tukey's HSD (honestly significantly difference) procedure. The results were assessed by the one-way analysis of variances using the Statistical Analysis System (SAS®, SAS Institute Inc., Cary, NC, USA). P < 0.05 was considered statistically significant.
| Results|| |
Action of gomisin A on [Ca2+]i
[Figure 1]a demonstrated that resting [Ca2+]i was 51 ± 1 nM. At 50–200 μM, gomisin A provoked [Ca2+]i raises in a dose-associated fashion. At 200 μM, gomisin A provoked [Ca2+]i raises of 40 ± 3 nM. The gomisin A-provoked Ca2+ signal saturated at 200 μM since 300 μM gomisin A failed to induce a greater signal (not shown). Further, in Ca2+-free medium, gomisin A induced raises in [Ca2+]i between 50 and 200 μM in a dose-associated fashion. At 200 μM, gomisin A elicited [Ca2+]i raises of 29 ± 2 nM [Figure 1]b. Shown in [Figure 1]c is dose-signal plots. Removing of extracellular Ca2+ diminished the Ca2+ response by 20%.
|Figure 1: Action of gomisin A on Ca2+ levels. (a) Gomisin A was administered at 25 s. The level of gomisin A was marked. The assays were conducted in Ca2+-containing solution. Y axis depicts the Ca2+ level provoked by gomisin A. (b) Action of gomisin A on Ca2+ levels in Ca2+-free solution. Gomisin A was administered at 25 s in Ca2+-free medium. Y axis is the [Ca2+]i raise provoked by gomisin A in the absence of Ca2+. (c) Dose-signal relationships of gomisin A-provoked [Ca2+]i raises in Ca2+-containing or -free medium. Y axis means the % of 200 μM gomisin A-provoked responses under the recording (25–250 s) of the [Ca2+]i raises in Ca2+-containig medium. Results are the standard error of the mean (SEM) of three independent assays. *P < 0.05 compared to empty circles.|
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Gomisin A-evoked Mn2+ entry reflected Ca2+ entry
The rationale of these experiments was that Mn2+ gets into cells via comparable routes as Ca2+ but smothers fluorescence at all excitation wavelengths (Merritt et al. 1989), whereas Ca2+ changes did not affect the fluorescence at 360 nm. As a result, smothering of fluorescence provoked at the Ca2+-insensitive excitation wavelength of 360 nm by Mn2+ implied Ca2+ entry. [Figure 2] demonstrates 200 μM gomisin A provoked an instant reduction in the 360 nm excitation response that reached a maximal level of 110 ± 2 random units within 130 s. It implicates Ca2+ entry occurred in gomisin A-induced [Ca2+]i raises.
|Figure 2: Action of gomisin A on Ca2+ entry by recording Mn2+ smothering of fluorescence. Assays were conducted in the presence of Ca2+. MnCl2 (50 μM) was administered to cells 1 min before recording. The Y-axis is arbitrary units recorded at the Ca2+-insensitive excitation wavelength of 360 nm and the emission wavelength of 510 nm. Trace a: control. Trace b: gomisin A (200 μM) was administered at time shown. Results are the SEM of three separate assays. SEM: standard error of the mean.|
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Modulation of gomisin A-induced [Ca2+]i raises
[Figure 1] depicts that gomisin A-evoked Ca2+ movement saturated at 200 μM; as a consequence in the next set of experiments, the signal evoked by 200 μM gomisin A was used as control. Phorbol 12-myristate 13 acetate (PMA; 1 nM; a PKC activator) and GF109203X (2 μM; a PKC inhibitor); econazole (0.5 μM), nifedipine (1 μM), and SKF96365 (5 μM) was respectively administrated 1 min prior to gomisin A (200 μM) in the presence of Ca2+. These chemicals suppressed gomisin A-evoked Ca2+ responses by approximately 20% [Figure 3].
|Figure 3: Action of Ca2+ channel regulators on gomisin A-evoked [Ca2+]i raises. In chemicals-incubated groups, the chemicals were administered 1 min before gomisin A (200 μM). The concentration was 10 nM for PMA, 2 μM for GF109203X, 1 μM for nifedipine, 0.5 μM for econazole, and 5 μM for SKF96365. Results were presented as % of control (1st column) which was the area under the recording (25-200 s) of 200 μM gomisin A-elicited [Ca2+]i raises in Ca2+-containing medium and were the SEM of three independent assays. *P < 0.05 in comparison to the 1st column, TG: Thapsigargin, SEM: Standard error of the mean.|
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Sources of gomisin A-evoked Ca2+ discharge
In cells, ER acts as the leading Ca2+ depository. Hence, the part of ER in gomisin A-provoked Ca2+ discharge in PC3 cells was investigated. To forbid interferences of Ca2+ entry, assays were performed in the absence of Ca2+. [Figure 4]a suggests that 1 μM thapsigargin, an ER Ca2+ pump selective suppressor, cause [Ca2+]i raises of 30 ± 1 nM. Gomisin A (200 μM) administrated at the time point of 500 s fell to evoke a Ca2+ response. On the contrary, after gomisin A (200 μM) evoked a Ca2+ signal, administration of 1 μM thapsigargin fell short to provoke [Ca2+]i raises [Figure 4]b.
|Figure 4: Action of thapsigargin on gomisin A-evoked Ca2+ discharge. (a and b) TG (1 μM) and gomisin A (200 μM) were administered as shown. Assays were conducted in Ca2+-free solution. Results were the SEM of three independent assays. TG: Thapsigargin, SEM: Standard error of the mean, ATP: Adenosine triphosphate.|
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Phospholipase C failed to have a part in gomisin A-evoked [Ca2+]i raises
PLC is a central protein that modulates discharge of Ca2+ from ER. Since gomisin A discharged Ca2+ from ER, the part that PLC played was investigated. U73122, a PLC suppressor, was chosen to examine if PLC was needed for gomisin A-induced Ca2+ discharge. [Figure 5]a depicts that ATP (4 μM) evoked [Ca2+]i raises of 20 ± 2 nM. ATP is a PLC-associated stimulator of [Ca2+]i raises in most cells. Mechanisms of ATP-induced calcium signaling and growth arrest in human prostate cancer cells. [Figure 5]b suggests that treatment with 2 μM U73122 failed to alter resting [Ca2+]i but extinguished ATP-provoked [Ca2+]i raises. It implied that U73122 successfully inhibited PLC. The findings depicted treatment with U73122 and ATP failed to alter 200 μM gomisin A-evoked [Ca2+]i raises. U73343 (2 μM), with a structure similar to U73122 without activity, was applied as control, fell short to inhibit ATP-provoked [Ca2+]i raises (unshown).
|Figure 5: Action of U73122 on gomisin A-evoked Ca2+ discharge. Assays were conducted in the absence of Ca2+. (a) ATP (4 μM) was administered at 25 s. (b) 1st column represents 200 μM gomisin A-provoked resting [Ca2+]i elevations. 2nd column means that 2 μM U73122 failed to change resting [Ca2+]i. 3st column means ATP-provoked [Ca2+]i raises. Fourth column means U73122 incubation for 1 min totally suppressed ATP-provoked [Ca2+]i raises. 5th column means U73122 (treatment for 1 min) and ATP (treatment for 30 s) co-incubation did not suppress 200 μM gomisin A-elicited [Ca2+]i raises. Results were the standard error of the mean of three independent assays. *P < 0.05 compared to paired bar. ATP: Adenosine triphosphate.|
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Gomisin A-induced cell death
Because gomisin A incubation evoked robust [Ca2+]i elevations, and uncontrolled [Ca2+]i elevations might lead to cytotoxicity, the following studies were performed to inspect effect of gomisin A on cytotoxicity. Cells were incubated with gomisin A overnight, the tetrazolium analysis was subsequently conducted. Cell number reduced in a dose-associated fashion in Ca2+-containing medium with 20–70 μM gomisin A [Figure 6].
|Figure 6: (a) After fura-2 loaded cells were treated with BAPTA/AM overnight, addition of 70 μM gomosin failed to evoke [Ca2+]i elevations. (b) Cytotoxicity of gomisin A. Cells were incubated with gomisin A (0–70 μM) overnight, and cytotoxicity assays were conducted. Results are % of control which is the augmentation in cell count in gomisin A-free groups. Control possesses 10,125 ± 212 cells/well prior to assays, and 13,754 ± 422 cells/well after pretreatment after 24 h. In each treatment, 5 μM BAPTA/AM was administrated to cells before pretreatment with gomisin A. Cytotoxicity assay was conducted afterward. Results are the SEM of three independent assays. SEM: Standard error of the mean. *P < 0.05 compared to the adjacent paired bar.|
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1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/acetoxy methyl did not curb gomisin A-caused cytotoxicity
Experiments were designed to explore whether the gomisin A-evoked cytotoxicity was induced by Ca2+. BAPTA/AM, a cytosolic Ca2+ chelator, was chosen to inhibit [Ca2+]i raises before gomisin A treatment. After pretreatment with BAPTA/AM (5 μM), 200 μM gomisin A fell short to provoke [Ca2+]i elevations (data unshown). The findings confirm that BAPTA/AM bound cytosolic Ca2+. [Figure 6] demonstrates that BAPTA/AM incubation failed to change resting values of viability. BAPTA/AM pretreatment fell to avoid gomisin A (20–70 μM)-caused cytotoxicity in the presence of gomisin A.
| Discussion|| |
The aim of current research was to inspect the action of gomisin A on Ca2+ movement and cytoxicity in prostate cells. A transient elevations of [Ca2+]i modulate many cellular responses in numerous cells. Our results suggest that gomisin A elevated [Ca2+]i. The Ca2+ response was consisted of Ca2+ influx and discharge from internal Ca2+ depot since it decreased by 20% in the absence of Ca2+. To further consolidate the data, the Mn2+ smothering data showed that Ca2+ influx was provoked throughout gomisin A preincubation.
Our results implicate that gomisin A-provoked [Ca2+]i elevations were suppressed (by 20%) by nifedipine, econazole or SKF96365. Literature shows that these chemicals are applied to suppress store-operated Ca2+ entry; even though selective inhibitors are presently unavailable.,, Thus, it appears that gomisin A evokes Ca2+ influx through store-operated Ca2+ entry, a procedure activated by discharge of Ca2+ depot. Since Ca2+ entry acts for 20% of gomisin A-provoked [Ca2+]i raises, PKC-sensitive Ca2+ entry and store-operated Ca2+ entry appears to play a significant role.
Protein kinases are thought to couple to Ca2+ signaling through different mechanisms. For example, the C2 domain of cPKCs is a Ca2+ sensor. Evidence suggests participation of PKC in elevations of [Ca2+]i in astrocytes.
Gomisin A-provoked [Ca2+]i raises were suppressed by either amplifying or suppressing PKC activity by 20%. Thus, gomisin A evoked a PKC-associated [Ca2+]i response, and basal activity of PKC was necessary for gomisin A to exert its maximal Ca2+ signal.
In terms of the Ca2+ depots associated with gomosin A-evoked Ca2+ discharge, ER store seemed to be involved. The Ca2+ stored in other organelles such as nuclei, mitochondria, Golgi bodies, cytoskeleton, etc., may release Ca2+ under different circumstances. Furthermore, the results also demonstrate that the Ca2+ discharge was via by a PLC-dissociated pathway, based on the finding that the discharge failed to be affected under the situation that PLC was inhibited. PLC-dissociated Ca2+ discharge routes have been reported. Lysophosphatidic acid increased [Ca2+]i by using the classical, PLC-dependent pathway as well as PLC-independent pathways.
Existence of cytosolic Ca2+ could alter cell viability. Evidence shows that specific combinations of ion channel inhibitors reduce excessive Ca2+ influx causing oxidative stress and increase in neuronal cell viability. Role of Ca2+-independent phospholipase A2 in complement-mediated glomerular epithelial cell injury was explored.
Our data results suggested gomisin A-provoked cytotoxicity is dissociated of [Ca2+]i raises since inhibition of [Ca2+]i rises failed to prevent cytotoxicity. Although gomisin A-elicited Ca2+ movement did not induce cytotoxicity, it may be able to alter Ca2+-sensitive procedures. Literature shows the action of maximum gomisin A level in human plasma has not been explored.
| Conclusion|| |
In sum, our findings implicate gomisin A elicited Ca2+ influx through PKC-dependent Ca2+ entry and store caused Ca2+ entry, and Ca2+ discharge from the endoplasmic reticulum in a PLC-dissociated manner. Gomisin A induced Ca2+-dissociated cytotoxicity.
Financial support and sponsorship
This work was supported by Kaohsiung Veterans General Hospital (KSVGH110-081) to Chen IS, Kaohsiung Veterans General Hospital Tainan Branch (VHYK110-02) to HLY, Kaohsiung Veterans General Hospital Tainan Branch (VHYK110-01) to LRA, Kaohsiung Veterans General Hospital (KSVGH110-140) to JCR, Ping Tung Christian Hospital (PS110001) to CJM.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]