Mitochondrial Ca2+ removal amplifies TRAIL cytotoxicity toward apoptosis-resistant tumor cells via promotion of multiple cell death modalities

Takata,Natsuhiko; Ohshima,Yohei; Suzuki-Karasaki,Miki; Yoshida,Yukihiro; Tokuhashi,Yasuaki; Suzuki-Karasaki,Yoshihiro

doi:10.3892/ijo.2017.4020

Mitochondrial Ca2+ removal amplifies TRAIL cytotoxicity toward apoptosis-resistant tumor cells via promotion of multiple cell death modalities

Authors:
- Natsuhiko Takata
- Yohei Ohshima
- Miki Suzuki-Karasaki
- Yukihiro Yoshida
- Yasuaki Tokuhashi
- Yoshihiro Suzuki-Karasaki
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Affiliations: Department of Orthopedic Surgery, Nihon University School of Medicine, Tokyo 173-8610, Japan, Plasma ChemiBio Laboratory, Nasushiobara, Tochigi 329-2813, Japan
Published online on: May 25, 2017 https://doi.org/10.3892/ijo.2017.4020
Pages: 193-203

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Abstract

Ca2+ has emerged as a new target for cancer treatment since tumor-specific traits in Ca2+ dynamics contributes to tumorigenesis, malignant phenotypes, drug resistance, and survival in different tumor types. However, Ca2+ has a dual (pro-death and pro-survival) function in tumor cells depending on the experimental conditions. Therefore, it is necessary to minimize the onset of the pro-survival Ca2+ signals caused by the therapy. For this purpose, a better understanding of pro-survival Ca2+ pathways in cancer cells is critical. Here we report that Ca2+ protects malignant melanoma (MM) and osteosarcoma (OS) cells from tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) cytotoxicity. Simultaneous measurements using the site-specific Ca2+ probes showed that acute TRAIL treatment rapidly and dose-dependently increased the cytosolic Ca2+ concentration ([Ca2+]cyt) and mitochondrial Ca2+ concentration ([Ca2+]mit) Pharmacological analyses revealed that the [Ca2+]mit remodeling was under control of mitochondrial Ca2+ uniporter (MCU), mitochondrial permeability transition pore (MPTP), and a Ca2+ transport pathway sensitive to capsazepine and AMG9810. Ca2+ chelators and the MCU inhibitor ruthenium 360, an MPTP opener atractyloside, capsazepine, and AMG9810 all decreased [Ca2+]mit and sensitized these tumor cells to TRAIL cytotoxicity. The Ca2+ modulation enhanced both apoptotic and non-apoptotic cell death. Although the [Ca2+]mit reduction potentiated TRAIL-induced caspase-3/7 activation and cell membrane damage within 24 h, this potentiation of cell death became pronounced at 72 h, and not blocked by caspase inhibition. Our findings suggest that in MM and OS cells mitochondrial Ca2+ removal can promote apoptosis and non-apoptotic cell death induction by TRAIL. Therefore, mitochondrial Ca2+ removal can be exploited to overcome the resistance of these cancers to TRAIL.

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1	Ivanov VN, Bhoumik A and Ronai Z: Death receptors and melanoma resistance to apoptosis. Oncogene. 22:3152–3161. 2003. View Article : Google Scholar : PubMed/NCBI
2	Guiho R, Biteau K, Heymann D and Redini F: TRAIL-based therapy in pediatric bone tumors: How to overcome resistance. Future Oncol. 11:535–542. 2015. View Article : Google Scholar : PubMed/NCBI
3	Ashkenazi A: Targeting the extrinsic apoptosis pathway in cancer. Cytokine Growth Factor Rev. 19:325–331. 2008. View Article : Google Scholar : PubMed/NCBI
4	Amarante-Mendes GP and Griffith TS: Therapeutic applications of TRAIL receptor agonists in cancer and beyond. Pharmacol Ther. 155:117–131. 2015. View Article : Google Scholar : PubMed/NCBI
5	de Miguel D, Lemke J, Anel A, Walczak H and Martinez-Lostao L: Onto better TRAILs for cancer treatment. Cell Death Differ. 23:733–747. 2016. View Article : Google Scholar : PubMed/NCBI
6	Wang S: The promise of cancer therapeutics targeting the TNF-related apoptosis-inducing ligand and TRAIL receptor pathway. Oncogene. 27:6207–6215. 2008. View Article : Google Scholar : PubMed/NCBI
7	Sayers TJ: Targeting the extrinsic apoptosis signaling pathway for cancer therapy. Cancer Immunol Immunother. 60:1173–1180. 2011. View Article : Google Scholar : PubMed/NCBI
8	Herrero-Martín G, Høyer-Hansen M, García-García C, Fumarola C, Farkas T, López-Rivas A and Jäättelä M: TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells. EMBO J. 28:677–685. 2009. View Article : Google Scholar : PubMed/NCBI
9	He W, Wang Q, Xu J, Xu X, Padilla MT, Ren G, Gou X and Lin Y: Attenuation of TNFSF10/TRAIL-induced apoptosis by an autophagic survival pathway involving TRAF2- and RIPK1/RIP1-mediated MAPK8/JNK activation. Autophagy. 8:1811–1821. 2012. View Article : Google Scholar : PubMed/NCBI
10	Jouan-Lanhouet S, Arshad MI, Piquet-Pellorce C, Martin-Chouly C, Le Moigne-Muller G, Van Herreweghe F, Takahashi N, Sergent O, Lagadic-Gossmann D, Vandenabeele P, et al: TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation. Cell Death Differ. 19:2003–2014. 2012. View Article : Google Scholar : PubMed/NCBI
11	Sosna J, Philipp S, Fuchslocher Chico J, Saggau C, Fritsch J, Föll A, Plenge J, Arenz C, Pinkert T, Kalthoff H, et al: Differences and similarities in TRAIL- and tumor necrosis factor-mediated necroptotic signaling in cancer cells. Mol Cell Biol. 36:2626–2644. 2016. View Article : Google Scholar : PubMed/NCBI
12	Dimberg LY, Anderson CK, Camidge R, Behbakht K, Thorburn A and Ford HL: On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics. Oncogene. 32:1341–1350. 2013. View Article : Google Scholar
13	Hempel N and Trebak M: Crosstalk between calcium and reactive oxygen species signaling in cancer. Cell Calcium. Jan 18–2017.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI
14	Villalobos C, Sobradillo D, Hernández-Morales M and Núñez L: Calcium remodeling in colorectal cancer. Biochim Biophys Acta. 1864:843–849. 2017. View Article : Google Scholar : PubMed/NCBI
15	Danese A, Patergnani S, Bonora M, Wieckowski MR, Previati M, Giorgi C and Pinton P: Calcium regulates cell death in cancer: Roles of the mitochondria and mitochondria-associated membranes (MAMs). Biochim Biophys Acta. Jan 10–2017.Epub ahead of print. View Article : Google Scholar
16	Nilius B and Szallasi A: Transient receptor potential channels as drug targets: From the science of basic research to the art of medicine. Pharmacol Rev. 66:676–814. 2014. View Article : Google Scholar : PubMed/NCBI
17	Orrenius S, Gogvadze V and Zhivotovsky B: Calcium and mitochondria in the regulation of cell death. Biochem Biophys Res Commun. 460:72–81. 2015. View Article : Google Scholar : PubMed/NCBI
18	Storr SJ, Carragher NO, Frame MC, Parr T and Martin SG: The calpain system and cancer. Nat Rev Cancer. 11:364–374. 2011. View Article : Google Scholar : PubMed/NCBI
19	Moretti D, Del Bello B, Allavena G and Maellaro E: Calpains and cancer: Friends or enemies? Arch Biochem Biophys. 564:26–36. 2014. View Article : Google Scholar : PubMed/NCBI
20	Akita M, Suzuki-Karasaki M, Fujiwara K, Nakagawa C, Soma M, Yoshida Y, Ochiai T, Tokuhashi Y and Suzuki-Karasaki Y: Mitochondrial division inhibitor-1 induces mitochondrial hyperfusion and sensitizes human cancer cells to TRAIL-induced apoptosis. Int J Oncol. 45:1901–1912. 2014.PubMed/NCBI
21	Suzuki Y, Inoue T, Murai M, Suzuki-Karasaki M, Ochiai T and Ra C: Depolarization potentiates TRAIL-induced apoptosis in human melanoma cells: Role for ATP-sensitive K⁺ channels and endoplasmic reticulum stress. Int J Oncol. 41:465–475. 2012.PubMed/NCBI
22	Suzuki Y, Yoshimaru T, Inoue T and Ra C: Mitochondrial Ca²⁺ flux is a critical determinant of the Ca²⁺ dependence of mast cell degranulation. J Leukoc Biol. 79:508–518. 2006. View Article : Google Scholar
23	Marchi S and Pinton P: The mitochondrial calcium uniporter complex: Molecular components, structure and physiopathological implications. J Physiol. 592:829–839. 2014. View Article : Google Scholar :
24	Tosatto A, Sommaggio R, Kummerow C, Bentham RB, Blacker TS, Berecz T, Duchen MR, Rosato A, Bogeski I, Szabadkai G, et al: The mitochondrial calcium uniporter regulates breast cancer progression via HIF-1α. EMBO Mol Med. 8:569–585. 2016. View Article : Google Scholar : PubMed/NCBI
25	Yang X, Wang B, Zeng H, Cai C, Hu Q, Cai S, Xu L, Meng X and Zou F: Role of the mitochondrial Ca²⁺ uniporter in Pb²⁺-induced oxidative stress in human neuroblastoma cells. Brain Res. 1575:12–21. 2014. View Article : Google Scholar : PubMed/NCBI
26	Tochigi M, Inoue T, Suzuki-Karasaki M, Ochiai T, Ra C and Suzuki-Karasaki Y: Hydrogen peroxide induces cell death in human TRAIL-resistant melanoma through intracellular superoxide generation. Int J Oncol. 42:863–872. 2013.PubMed/NCBI
27	Curry MC, Peters AA, Kenny PA, Roberts-Thomson SJ and Monteith GR: Mitochondrial calcium uniporter silencing potentiates caspase-independent cell death in MDA-MB-231 breast cancer cells. Biochem Biophys Res Commun. 434:695–700. 2013. View Article : Google Scholar : PubMed/NCBI
28	De Stefani D, Patron M and Rizzuto R: Structure and function of the mitochondrial calcium uniporter complex. Biochim Biophys Acta. 1853:2006–2011. 2015. View Article : Google Scholar : PubMed/NCBI
29	Brand MD: Electroneutral efflux of Ca²⁺ from liver mitochondria. Biochem J. 225:413–419. 1985. View Article : Google Scholar : PubMed/NCBI
30	Altschuld RA, Hohl CM, Castillo LC, Garleb AA, Starling RC and Brierley GP: Cyclosporin inhibits mitochondrial calcium efflux in isolated adult rat ventricular cardiomyocytes. Am J Physiol. 262:H1699–H1704. 1992.PubMed/NCBI
31	Bernardi P and von Stockum S: The permeability transition pore as a Ca²⁺ release channel: New answers to an old question. Cell Calcium. 52:22–27. 2012. View Article : Google Scholar : PubMed/NCBI
32	Di Lisa F, Carpi A, Giorgio V and Bernardi P: The mitochondrial permeability transition pore and cyclophilin D in cardioprotection. Biochim Biophys Acta. 1813:1316–1322. 2011. View Article : Google Scholar : PubMed/NCBI
33	Gutiérrez-Aguilar M and Baines CP: Structural mechanisms of cyclophilin D-dependent control of the mitochondrial permeability transition pore. Biochim Biophys Acta. 1850:2041–2047. 2015. View Article : Google Scholar :
34	Klingenberg M: The ADP and ATP transport in mitochondria and its carrier. Biochim Biophys Acta. 1778:1978–2021. 2008. View Article : Google Scholar : PubMed/NCBI
35	Zamorano S, Rojas-Rivera D, Lisbona F, Parra V, Court FA, Villegas R, Cheng EH, Korsmeyer SJ, Lavandero S and Hetz C: A BAX/BAK and cyclophilin D-independent intrinsic apoptosis pathway. PLoS One. 7:e377822012. View Article : Google Scholar : PubMed/NCBI
36	Briston T, Lewis S, Koglin M, Mistry K, Shen Y, Hartopp N, Katsumata R, Fukumoto H, Duchen MR, Szabadkai G, et al: Identification of ER-000444793, a Cyclophilin D-independent inhibitor of mitochondrial permeability transition, using a high-throughput screen in cryopreserved mitochondria. Sci Rep. 6:377982016. View Article : Google Scholar : PubMed/NCBI
37	Bevan S, Hothi S, Hughes G, James IF, Rang HP, Shah K, Walpole CS and Yeats JC: Capsazepine: A competitive antagonist of the sensory neurone excitant capsaicin. Br J Pharmacol. 107:544–552. 1992. View Article : Google Scholar : PubMed/NCBI
38	Gavva NR, Tamir R, Qu Y, Klionsky L, Zhang TJ, Immke D, Wang J, Zhu D, Vanderah TW, Porreca F, et al: AMG 9810 [(E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonist with antihyperalgesic properties. J Pharmacol Exp Ther. 313:474–484. 2005. View Article : Google Scholar
39	Zhao R and Tsang SY: Versatile roles of intracellularly located TRPV1 channel. J Cell Physiol. 232:1957–1965. 2017. View Article : Google Scholar
40	Thomas KC, Roberts JK, Deering-Rice CE, Romero EG, Dull RO, Lee J, Yost GS and Reilly CA: Contributions of TRPV1, endovanilloids, and endoplasmic reticulum stress in lung cell death in vitro and lung injury. Am J Physiol Lung Cell Mol Physiol. 302:L111–L119. 2012. View Article : Google Scholar :
41	Stock K, Kumar J, Synowitz M, Petrosino S, Imperatore R, Smith ES, Wend P, Purfürst B, Nuber UA, Gurok U, et al: Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1. Nat Med. 18:1232–1238. 2012. View Article : Google Scholar : PubMed/NCBI
42	Mellier G and Pervaiz S: The three Rs along the TRAIL: Resistance, re-sensitization and reactive oxygen species (ROS). Free Radic Res. 46:996–1003. 2012. View Article : Google Scholar : PubMed/NCBI
43	Suzuki-Karasaki M, Ochiai T and Suzuki-Karasaki Y: Crosstalk between mitochondrial ROS and depolarization in the potentiation of TRAIL-induced apoptosis in human tumor cells. Int J Oncol. 44:616–628. 2014.
44	Voltan R, Secchiero P, Casciano F, Milani D, Zauli G and Tisato V: Redox signaling and oxidative stress: Cross talk with TNF-related apoptosis inducing ligand activity. Int J Biochem Cell Biol. 81:364–374. 2016. View Article : Google Scholar : PubMed/NCBI
45	Kozai D, Ogawa N and Mori Y: Redox regulation of transient receptor potential channels. Antioxid Redox Signal. 21:971–986. 2014. View Article : Google Scholar
46	Mergler S, Derckx R, Reinach PS, Garreis F, Böhm A, Schmelzer L, Skosyrski S, Ramesh N, Abdelmessih S, Polat OK, et al: Calcium regulation by temperature-sensitive transient receptor potential channels in human uveal melanoma cells. Cell Signal. 26:56–69. 2014. View Article : Google Scholar
47	Chien CS, Ma KH, Lee HS, Liu PS, Li YH, Huang YS and Chueh SH: Dual effect of capsaicin on cell death in human osteosarcoma G292 cells. Eur J Pharmacol. 718:350–360. 2013. View Article : Google Scholar : PubMed/NCBI
48	Marchi S, Lupini L, Patergnani S, Rimessi A, Missiroli S, Bonora M, Bononi A, Corrà F, Giorgi C, De Marchi E, et al: Downregulation of the mitochondrial calcium uniporter by cancer-related miR-25. Curr Biol. 23:58–63. 2013. View Article : Google Scholar :