Aspirin Induces Mitochondrial Ca2+ Remodeling in Tumor Cells via ROS‒Depolarization‒Voltage-Gated Ca2+ Entry
Abstract
:1. Introduction
2. Results
2.1. Aspirin and Salicylate Reduce Tumor Cell Viability in a ROS-Dependent Manner
2.2. Aspirin and Salicylate Induce Apoptotic and Necrotic Cell Death
2.3. Aspirin and Salicylate Induce Mitochondrial Dysfunction
2.4. Aspirin Rapidly Evokes Depolarization in a ROS-Dependent Manner
2.5. Ca2+ Regulates the Anti-Melanoma Effect of Aspirin
2.6. Aspirin Modulates the Intracellular Ca2+ Dynamics
2.7. Cav1.2 Downregulation Inhibits the Effect of Aspirin on Ca2+m
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. Cell Culture
4.3. Cell Viability Assay
4.4. Measurements of ROS Generation in Live Cells
4.5. Cell Death Assay
4.6. Intracellular Ca2+ Measurements
4.7. Measurement of Depolarization
4.8. Gene Expression Analyses
4.9. Gene Silencing by RNA Interference
4.10. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Dhillon, S. Dabrafenib plus Trametinib: A Review in Advanced Melanoma with a BRAF (V600) Mutation. Target. Oncol. 2016, 11, 417–428. [Google Scholar] [CrossRef] [PubMed]
- Weber, J.S.; D’Angelo, S.P.; Minor, D.; Hodi, F.S.; Gutzmer, R.; Neyns, B.; Hoeller, C.; Khushalani, N.I.; Miller, W.H., Jr.; Lao, C.D.; et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2016, 16, 375–384. [Google Scholar] [CrossRef]
- Weber, J.; Mandala, M.; Del Vecchio, M.; Gogas, H.J.; Arance, A.M.; Cowey, C.L.; Dalle, S.; Schenker, M.; Chiarion-Sileni, V.; Marquez-Rodas, I.; et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N. Eng. J. Med. 2017, 377, 1824–2835. [Google Scholar] [CrossRef] [PubMed]
- Vane, J.R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat. New Biol. 1971, 231, 232–235. [Google Scholar] [CrossRef]
- Ulrich, C.M.; Bigler, J.; Potter, J.D. Non-steroidal anti-inflammatory drugs for cancer prevention: Promise, perils and pharmacogenetics. Nat. Rev. Cancer 2006, 6, 130–140. [Google Scholar] [CrossRef]
- Tegeder, I.; Pfeilschifter, J.; Geisslinger, G. Cyclooxygenase-independent actions of cyclooxygenase inhibitors. FASEB J. 2001, 15, 2057–2072. [Google Scholar] [CrossRef]
- Jana, N.R. NSAIDs and apoptosis. Cell Mol. Life Sci. 2008, 65, 1295–1301. [Google Scholar] [CrossRef]
- Ordan, O.; Rotem, R.; Jaspers, I.; Flescher, E. Stress-responsive JNK mitogen-activated protein kinase mediates aspirin-induced suppression of B16 melanoma cellular proliferation. Br. J. Pharmacol. 2003, 138, 1156–1162. [Google Scholar] [CrossRef] [Green Version]
- Tsai, C.S.; Luo, S.F.; Ning, C.C.; Lin, C.L.; Jiang, M.C.; Liao, C.F. Acetylsalicylic acid regulates MMP-2 activity and inhibits colorectal invasion of murine B16F0 melanoma cells in C57BL/6J mice: Effects of prostaglandin F(2)alpha. Biomed. Pharmacother. 2009, 63, 522–527. [Google Scholar] [CrossRef]
- Vad, N.M.; Kudugunti, S.K.; Wang, H.; Bhat, G.J.; Moridani, M.Y. Efficacy of acetylsalicylic acid (aspirin) in skin B16-F0 melanoma tumor-bearing C57BL/6 mice. Tumour Biol. 2014, 35, 4967–4976. [Google Scholar] [CrossRef]
- Zelenay, S.; van der Veen, A.G.; Böttcher, J.P.; Snelgrove, K.J.; Rogers, N.; Acton, S.E.; Chakravarty, P.; Girotti, M.R.; Marais, R.; Quezada, S.A.; et al. Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity. Cell 2015, 162, 1257–1270. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Thyagarajan, A.; Saylae, J.; Sahu, R.P. Acetylsalicylic acid inhibits the growth of melanoma tumors via SOX2-dependent-PAF-R-independent signaling pathway. Oncotarget 2017, 8, 49959. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McCarthy, J.V.; Cotter, T.G. Cell shrinkage and apoptosis: A role for potassium and sodium ion efflux. Cell Death Differ. 1997, 4, 756–770. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lang, F.; Föller, M.; Lang, K.; Lang, P.; Ritter, M.; Vereninov, A.; Szabo, I.; Huber, S.M.; Gulbins, E. Cell volume regulatory ion channels in cell proliferation and cell death. Methods Enzymol. 2007, 428, 209–225. [Google Scholar]
- Bortner, C.D.; Gomez-Angelats, M.; Cidlowski, J.A. Plasma membrane depolarization without repolarization is an early molecular event in anti-Fas-induced apoptosis. J. Biol. Chem. 2001, 276, 4304–4314. [Google Scholar] [CrossRef] [Green Version]
- Yin, W.; Li, X.; Feng, S.; Cheng, W.; Tang, B.; Shi, Y.L.; Hua, Z.C. Plasma membrane depolarization and Na,K-ATPase impairment induced by mitochondrial toxins augment leukemia cell apoptosis via a novel mitochondrial amplification mechanism. Biochem. Pharmacol. 2009, 78, 191–202. [Google Scholar] [CrossRef]
- Nolte, F.; Friedrich, O.; Rojewski, M.; Fink, R.H.; Schrezenmeier, H.; Körper, S. Depolarisation of the plasma membrane in the arsenic trioxide (As2O3)-and anti-CD95-induced apoptosis in myeloid cells. FEBS Lett. 2004, 578, 85–89. [Google Scholar] [CrossRef] [Green Version]
- Suzuki, Y.; Inoue, T.; Murai, M.; Suzuki-Karasaki, M.; Ochiai, T.; Ra, C. Depolarization potentiates TRAIL-induced apoptosis in human melanoma cells: Role for ATP-sensitive K+ channels and endoplasmic reticulum stress. Int. J. Oncol. 2012, 41, 465–475. [Google Scholar] [CrossRef]
- Inoue, T.; Suzuki-Karasaki, Y. Mitochondrial superoxide mediates mitochondrial and endoplasmic reticulum dysfunctions in TRAIL-induced apoptosis in Jurkat cells. Free Radic. Biol. Med. 2013, 61, 273–284. [Google Scholar] [CrossRef]
- Suzuki-Karasaki, M.; Ochiai, T.; Suzuki-Karasaki, Y. Crosstalk between mitochondrial ROS and depolarization in the potentiation of TRAIL-induced apoptosis in human tumor cells. Int. J. Oncol. 2014, 44, 616–628. [Google Scholar] [CrossRef] [Green Version]
- Suzuki-Karasaki, Y.; Fujiwara, K.; Saito, K.; Suzuki-Karasaki, M.; Ochiai, T.; Soma, M. Distinct effects of TRAIL on the mitochondrial network in human cancer cells and normal cells: Role of plasma membrane depolarization. Oncotarget 2015, 6, 21572. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ghoumari, A.M.; Piochon, C.; Tomkiewicz, C.; Eychenne, B.; Levenes, C.; Dusart, I.; Schumacher, M.; Baulieu, E.E. Neuroprotective effect of mifepristone involves neuron depolarization. FASEB J. 2006, 20, 1377–1386. [Google Scholar] [CrossRef] [PubMed]
- Núñez, L.; Valero, R.A.; Senovilla, L.; Sanz-Blasco, S.; García-Sancho, J.; Villalobos, C. Cell proliferation depends on mitochondrial Ca2+ uptake: Inhibition by salicylate. J. Physiol. 2006, 571, 57–73. [Google Scholar] [CrossRef] [PubMed]
- Trost, L.C.; Lemasters, J.J. Role of the mitochondrial permeability transition in salicylate toxicity to cultured rat hepatocytes: Implications for the pathogenesis of Reye’s syndrome. Toxicol. Appl. Pharmacol. 1997, 147, 431–441. [Google Scholar] [CrossRef] [PubMed]
- Zhang, H.; Lu, J.; Jiao, Y.; Chen, Q.; Li, M.; Wang, Z.; Yu, Z.; Huang, X.; Yao, A.; Gao, Q.; et al. Aspirin Inhibits Natural Killer/T-Cell Lymphoma by Modulation of VEGF Expression and Mitochondrial Function. Front. Oncol. 2019, 8, 679. [Google Scholar] [CrossRef] [Green Version]
- Barry, E.L. Expression of mRNAs for the alpha 1 subunit of voltage-gated calcium channels in human osteoblast-like cell lines and in normal human osteoblasts. Calcif. Tissue Int. 2000, 66, 145–150. [Google Scholar] [CrossRef]
- Wang, X.T.; Nagaba, Y.; Cross, H.S.; Wrba, F.; Zhang, L.; Guggino, S.E. The mRNA of l-type calcium channel elevated in colon cancer: Protein distribution in normal and cancerous colon. Am. J. Pathol. 2000, 157, 1549–1562. [Google Scholar] [CrossRef]
- Das, A.; Pushparaj, C.; Bahí, N.; Sorolla, A.; Herreros, J.; Pamplona, R.; Vilella, R.; Matias-Guiu, X.; Martí, R.M.; Cantí, C. Functional expression of voltage-gated calcium channels in human melanoma. Pigment Cell Melanoma Res. 2012, 25, 200–212. [Google Scholar] [CrossRef]
- Elustondo, P.A.; Nichols, M.; Robertson, G.S.; Pavlov, E.V. Mitochondrial Ca2+ uptake pathways. J. Bioenergy Biomembr. 2017, 49, 113–119. [Google Scholar] [CrossRef]
- Orrenius, S.; Gogvadze, V.; Zhivotovsky, B. Mitochondrial oxidative stress: Implications for cell death. Annu. Rev. Pharmacol. Toxicol. 2007, 47, 143–183. [Google Scholar] [CrossRef]
- Ralph, S.J.; Rodríguez-Enríquez, S.; Neuzil, J.; Moreno-Sánchez, R. Bioenergetic pathways in tumor mitochondria as targets for cancer therapy and the importance of the ROS-induced apoptotic trigger. Mol. Asp. Med. 2010, 31, 29–59. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lemasters, J.J.; Theruvath, T.P.; Zhong, Z.; Nieminen, A.L. Mitochondrial calcium and the permeability transition in cell death. Biochim. Biophys. Acta 2009, 1787, 1395–1401. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhu, L.P.; Yu, X.D.; Ling, S.; Brown, R.A.; Kuo, T.H. Mitochondrial Ca2+ homeostasis in the regulation of apoptotic and necrotic cell deaths. Cell Calcium 2000, 28, 107–117. [Google Scholar] [CrossRef] [PubMed]
- Prakriya, M.; Lewis, R.S. Store-Operated Calcium Channels. Physiol. Rev. 2015, 95, 1383–1436. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jardin, I.; Rosado, J.A. STIM and calcium channel complexes in cancer. Biochim. Biophys. Acta 2016, 1863, 1418–1426. [Google Scholar] [CrossRef] [PubMed]
- Chalmers, S.B.; Monteith, G.R. ORAI channels and cancer. Cell Calcium 2018, 74, 160–167. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Deak, A.T.; Blass, S.; Khan, M.J.; Groschner, L.N.; Waldeck-Weiermair, M.; Hallström, S.; Graier, W.F.; Malli, R. IP3-mediated STIM1 oligomerization requires intact mitochondrial Ca2+ uptake. J. Cell Sci. 2014, 127, 2944–2955. [Google Scholar] [CrossRef] [Green Version]
- Takata, N.; Ohshima, Y.; Suzuki-Karasaki, M.; Yoshida, Y.; Tokuhashi, Y.; Suzuki-Karasaki, Y. Mitochondrial Ca2+ removal amplifies TRAIL cytotoxicity toward apoptosis-resistant tumor cells via promotion of multiple cell death modalities. Int. J. Oncol. 2017, 51, 193–203. [Google Scholar] [CrossRef]
- Nakagawa, C.; Suzuki-Karasaki, M.; Suzuki-Karasaki, M.; Ochiai, T.; Suzuki-Karasaki, Y. The Mitochondrial Ca2+ Overload via Voltage-Gated Ca2+ Entry Contributes to an Anti-Melanoma Effect of Diallyl Trisulfide. Int. J. Mol. Sci. 2020, 21, 491. [Google Scholar] [CrossRef] [Green Version]
- Wang, Y.; Deng, X.; Mancarella, S.; Hendron, E.; Eguchi, S.; Soboloff, J.; Tang, X.D.; Gill, D.L. The calcium store sensor, STIM1, reciprocally controls Orai and CaV1.2 channels. Science 2010, 330, 105–109. [Google Scholar] [CrossRef] [Green Version]
- Dionisio, N.; Smani, T.; Woodard, G.E.; Castellano, A.; Salido, G.M.; Rosado, J.A. Homer proteins mediate the interaction between STIM1 and Cav1.2 channels. Biochim. Biophys. Acta 2015, 1853, 1145–1153. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ohshima, Y.; Takata, N.; Suzuki-Karasaki, M.; Yoshida, Y.; Tokuhashi, Y.; Suzuki-Karasaki, Y. Disrupting mitochondrial Ca2+ homeostasis causes tumor-selective TRAIL sensitization through mitochondrial network abnormalities. Int. J. Oncol. 2017, 51, 1146–1158. [Google Scholar] [CrossRef] [PubMed]
- Ruiz, A.; Alberdi, E.; Matute, C. CGP37157, an inhibitor of the mitochondrial Na+/Ca2+ exchanger, protects neurons from excitotoxicity by blocking voltage-gated Ca2+ channels. Cell Death Dis. 2014, 5, e1156. [Google Scholar] [CrossRef] [PubMed] [Green Version]
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Fujikawa, I.; Ando, T.; Suzuki-Karasaki, M.; Suzuki-Karasaki, M.; Ochiai, T.; Suzuki-Karasaki, Y. Aspirin Induces Mitochondrial Ca2+ Remodeling in Tumor Cells via ROS‒Depolarization‒Voltage-Gated Ca2+ Entry. Int. J. Mol. Sci. 2020, 21, 4771. https://doi.org/10.3390/ijms21134771
Fujikawa I, Ando T, Suzuki-Karasaki M, Suzuki-Karasaki M, Ochiai T, Suzuki-Karasaki Y. Aspirin Induces Mitochondrial Ca2+ Remodeling in Tumor Cells via ROS‒Depolarization‒Voltage-Gated Ca2+ Entry. International Journal of Molecular Sciences. 2020; 21(13):4771. https://doi.org/10.3390/ijms21134771
Chicago/Turabian StyleFujikawa, Itsuho, Takashi Ando, Manami Suzuki-Karasaki, Miki Suzuki-Karasaki, Toyoko Ochiai, and Yoshihiro Suzuki-Karasaki. 2020. "Aspirin Induces Mitochondrial Ca2+ Remodeling in Tumor Cells via ROS‒Depolarization‒Voltage-Gated Ca2+ Entry" International Journal of Molecular Sciences 21, no. 13: 4771. https://doi.org/10.3390/ijms21134771