Differential Regulation of Cytochrome C Release in Dexamethasone-Resistant 7TD1 Cells


Interleukin-6 (IL6)-triggered JAK/STAT3 and PI3K/AKT signaling pathways are known to mediate cell survival, drug resistance and progression in a variety of cancer cells. Resistance to induction of apoptosis plays a critical role in the pathogenesis of numerous cancers and development of resistance to chemotherapeutic agents used in its treatment. Previous research in our laboratory employing a dexamethasone-resistant subline (7TD1-Dxm) of IL6-dependent 7TD1 cells indicated that constitutively activated STAT3 was important in control of apoptosis and targets downstream to activated STAT3 appeared to be involved in the development of resistance to dexamethasone by 7TD1 cells. We therefore investigated the hypothesis that Dxm-resistance developed by 7TD1-Dxm cells was due to resistance to induction of apoptosis mainly because of the dysregulation of the downstream targeted in JAK/STAT3 signaling pathway. Our results indicate that 7TD1-Dxm cells show resistance to Dxm-induced reduction of Bcl-2 protein and the release of cytochrome c. Thus, this study suggests that development of resistance to dexamethasone by 7TD1 cells may involve altered regulation of mitochondrial anti-apoptotic proteins.

Share and Cite:

K. Gangavarapu, A. Bhushan, J. Lai and C. Daniels, "Differential Regulation of Cytochrome C Release in Dexamethasone-Resistant 7TD1 Cells," Journal of Cancer Therapy, Vol. 4 No. 4, 2013, pp. 835-842. doi: 10.4236/jct.2013.44095.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] A. G. Moses, J. Maingay, K. Sangster, K. C. Fearon and J. A. Ross, “Proinflammatory Cytokine Release by Peripheral Blood Mononuclear Cells from Patients with Advanced Pancreatic Cancer: Relationship to Acute Phase Response and Survival,” Oncology Reports, Vol. 21, No. 4, 2009, pp. 1091-1095.
[2] Y. Y. Li, L. L. Hsieh, R. P. Tang, S. K. Liao and K. Y. Yeh, “Interleukin-6 (IL-6) Released by Macrophages Induces IL-6 Secretion in the Human Colon Cancer HT-29 Cell Line,” Human Immunology, Vol. 70, No. 3, 2009, pp. 151-158. doi:10.1016/j.humimm.2009.01.004
[3] M. Colombatti, S. Grasso, A. Porzia, G. Fracasso, M. Y. Scupoli, S. Cingarlini, O. Poffe, H. Y. Naim, M. Heine, G. Tridente, F. Mainiero and D. Ramarli, “The Prostate Specific Membrane Antigen Regulates the Expression of IL-6 and CCL5 in Prostate Tumour Cells by Activating the MAPK Pathways,” PLoS One, Vol. 4, No. 2, 2009, p. e4608. doi:10.1371/journal.pone.0004608
[4] S. Feng, Q. Tang, M. Sun, J. Y. Chun, C. P. Evans and A. C. Gao, “Interleukin-6 Increases Prostate Cancer Cells Resistance to Bicalutamide via TIF2,” Molecular Cancer Therapy, Vol. 8, No. 3, 2009, pp. 665-671. doi:10.1158/1535-7163.MCT-08-0823
[5] M. Hallek, L. Bergsagel and K. C. Anderson, “Multiple Myeloma: Increasing Evidence for a Multistep Transformation Process,” Blood, Vol. 91, No. 1, 1998, pp. 3-21.
[6] R. A. Kyle and S. V. Rajkumar, “Multiple Myeloma,” Blood, Vol. 111, No. 5, 2008, pp. 2962-2972. doi:10.1182/blood-2007-10-078022
[7] K. C. Anderson, “Moving Disease Biology from the Lab to the Clinic,” Cancer, Vol. 97, No. 3, 2003, pp. 796-801. doi:10.1002/cncr.11137
[8] D. Chauhan, P. Pandey, T. Hideshima, S. Treon, N. Raje, F. E. Davies, Y. Shima, Y. T. Tai, S. Rosen, S. Avraham, S. Kharbanda and K. C. Anderson, “SHP2 Mediates the Protective Effect of Interleukin-6 against DexamethasoneInduced Apoptosis in Multiple Myeloma Cells,” Journal of Biological Chemistry, Vol. 275, 2000, pp. 27845-27850.
[9] D. Chauhan and K. C. Anderson, “Apoptosis in Multiple Myeloma: Therapeutic Implications,” Apoptosis, Vol. 6, No. 1-2, 2001, pp. 47-55. doi:10.1023/A:1009620027205
[10] T. Hideshima and K. C. Anderson, “Molecular Mechanisms of Novel Therapeutic Approaches for Multiple Myeloma,” Nature Reviews, Cancer, Vol. 2, No. 12, 2002, pp. 927-937. doi:10.1038/nrc952
[11] D. Chauhan and K. C. Anderson, “Mechanisms of Cell Death and Survival in Multiple Myeloma (MM): Therapeutic Implications,” Apoptosis, Vol. 8, No. 4, 2003, pp. 337-343. doi:10.1023/A:1024 164700094
[12] M. Oancea, A. Mani, M. A. Hussein and A. Almasan, “Apoptosis of Multiple Myeloma,” International Journal of Hematology, Vol. 80, No. 3, 2004, pp. 224-231. doi:10.1532/IJH97.04107
[13] Q. Chen, B. Gong, A. S. Mahmoud-Ahmed, A. Zhou, E. D. His, M. Hussein and A. Almasan, “Apo2L/TRAIL and Bcl-2-Related Proteins Regulate Type I Interferon-Induced Apoptosis in Multiple Myeloma,” Blood, Vol. 98, No. 7, 2001, pp. 2183-2192. doi:10.1182/blood.V98.7.2183
[14] Q. Chen, S. Ray, M. A. Hussein, G. Srkalovic and A. Almasan, “Role of Apo2L/TRAIL and Bcl-2 Family Proteins in Apoptosis of Multiple Myeloma,” Leukemia and Lymphoma, Vol. 44, No. 7, 2003, pp. 1209-1214. doi:10.1080/1042819031000068052
[15] B. Zhang, I. Gojo and R. G. Fenton, “Myeloid Cell Factor-1 Is a Critical Survival Factor for Multiple Myeloma,” Blood, Vol. 99, No. 5, 2002, pp. 1885-1893. doi:10.1182/blood.V99.6.1885
[16] Y. Tu, S. Renner, F. Xu, A. Fleishman, J. Taylor, J. Weisz, R. Vescio, M. Rettig, J. Berenson, S. Krajewski, J. C. Reed and A. Lichtenstein, “BCL-X Expression in Multiple Myeloma: Possible Indicator of Chemoresistance,” Cancer Research, Vol. 58, 1998, pp. 256-262.
[17] M. Linden, N. Kirchhof, C. Carlson and B. Van Ness, “Targeted Overexpression of BCL-XL in B-Lymphoid Cells Results in Lymphoproliferative Disease and Plasma Cell Malignancies,” Blood, Vol. 103, No. 7, 2004, pp. 2779-2786. doi:10.1182/blood-2003-10-3399
[18] R. Catlett-Falcone, T. H. Landowski, M. M. Oshiro, J. Turkson, A. Levitzki, R. Savino, G. Ciliberto, L. Moscinski, J. L. Fernandez-Luna, G. Nunez, W. S. Dalton and R. Jove, “Constitutive Activation of STAT3 Signaling Confers Resistance to Apoptosis in Human U266 Myeloma Cells,” Immunity, Vol. 10, No. 1, 1999, pp. 105-115. doi:10.1016/S1074-7613(00)80011-4
[19] A. K. Pathak, M. Bhutani, A. S. Nair, K. S. Ahn, A. Chakraborty, H. Kadara, S. Guha, G. Sethi and B. B. Aggarwal, “Urosilic Acid Inhibits STAT3 Activation Pathway Leading to Suppression of Proliferation and Chemosensitization of Human Multiple Myeloma Cells,” Molecular Cancer Research, Vol. 5, 2007, pp. 943-955. doi:10.1158/1541-7786.MCR-06-0348
[20] L. H. Wang, X. Y. Yang, X. Zhang, J. Huang, J. Hou, J. Li, H. Xiong, K. Mihalic, H. Zhu, W. Xiao and W. L. Farrar, “Transcriptional Inactivation of STAT3 by PPARγ Suppresses IL-6-Responsive Multiple Myeloma Cells,” Immunity, Vol. 20, No. 2, 2004, pp. 205-218. doi:10.1016/S1074-7613(04)00030-5
[21] L. Quintanilla-Martinez, M. Kremer, K. Specht, J. Calzada-Wack, M. Nathrath, R. Schaich, H. Hofler and F. Fend, “Analysis of Signal Transducer and Activator of Transcription 3 (STAT3) Pathway in Multiple Myeloma,” American Journal of Pathology, Vol. 162, No. 5, 2003, pp. 1449-1461. doi:10.1016/S0002-9440(10)64278-2
[22] K. J. Gangavarapu, J. L. Olbertz, A. Bhushan, J. C. K. Lai and C. K. Daniels, “Apoptotic Resistance Exhibited by Dexamethasone-Resistant Murine 7TD1 Cells Is Controlled Independently of Interleukin-6 Triggered Signaling,” Apoptosis, Vol. 13, No. 11, 2008, pp. 1394-1400. doi:10.1007/s10495-008-0265-y
[23] B. Irvin, C. Hanson, L. Smith and C. K. Daniels, “Cyclic Amp-IL6-Signaling Cross Talk: Comodulation of Proliferation and Apoptosis in the 7TD1 B Cell Hybridoma,” Experimental Cell Research, Vol. 265, No. 1, 2001, pp. 73-79. doi:10.1006/excr.2001.5157
[24] T. Mosmann, “Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assays,” Journal of Immunological Methods, Vol. 65, No. 1-2, 1983, pp. 55-63. doi:10.1016/0022-1759(83)90303-4
[25] E. R. Gauthier, L. Piche, G. Lemieux and R. Lemieux, “Role of bcl-Xl in the Control of Apoptosis in Murine Myeloma Cells,” Cancer Research, Vol. 56, No. 6, 1996, pp. 1451-1456.
[26] R. Khosravi-Far and M. D. Esposti, “Death Receptor Signals to Mitochondria,” Cancer Biology & Therapy, Vol. 3, No. 11, 2004, pp. 1051-1057. doi:10.4161/cbt.3.11.1173
[27] O. Von Ahsen, N. J. Waterhouse, T. Kuwana, D. D. Newmeyer and D. R. Green, “The ‘Harmless’ Release of Cytochrome C,” Cell Death and Differentiation, Vol. 7, No. 12, 2000, pp. 1192-1199. doi:10.1038/sj.cdd.4400782
[28] S.-M. Chiu and N. L. Oleinick, “Dissociation of Mitochondrial Depolarization form Cytochrome C Release during Apoptosis Induced by Photodynamic Therapy,” British Journal of Cancer, Vol. 84, 2001, pp. 1099-1106. doi:10.1054/bjoc.2000.1714
[29] D. M. Finucane, N. J. Waterhouse, G. P. Amarante-Mendes, T. G. Cotter and D. R. Green, “Collapse of the Inner Mitochondrial Transition Potential Is Not Required for Apoptosis in HL60 Cells,” Experimental Cell Research, Vol. 251, No. 1, 1999, pp. 166-174. doi:10.1006/excr.1999.4527
[30] D. M. Finucane, E. BossyWetzel, N. J. Waterhouse, T. G. Cotter and D. R. Green, “Bax-Induced Caspase Activation and Apoptosis via Cytochrome C Release from Mitochondria Is Inhibitable by Bcl-xL,” Journal of Biological Chemistry, Vol. 274, 1999, pp. 2225-2233. doi:10.1074/jbc.274.4.2225
[31] R. Eskes, B. Antonsson, A. Osen-Sand, S. Montessuit, C. Richter, R. Sadoul, G. Mazzei, A. Nichols and J.-C. Martinou, “Bax-Induced Cytochrome C Release form Mitochondria Is Independent of the Permeability Transition Pore but Highly Dependent on Mg2+ Ions,” Journal of Cell Biology, Vol. 143, No. 1, 1998, pp. 217-224. doi:10.1083/jcb.143.1.217
[32] R. M. Kluck, E. Bossy-Wetzel, D. R. Green and D. D. Newmeyer, “The Release of Cytochrome C from Mitochondria: A Primary Site for Bcl-2 Regulation of Apoptosis,” Science, Vol. 275. No. 5303, 1997, pp. 1132-1136. doi:10.1126/science.275.5303.1132
[33] A. Muto, M. Hori, Y. Sasaki, A. Saitoh, I. Yasuda, T. Maekawa, T. Uchida, K. Asakura, T. Nakazato, T. Kaneda, M. Kizaki, Y. Ikeda and T. Yoshida, “Emodin Has a Cytotoxic Effect against Human Multiple Myeloma as a Janus-Activated Kinase 2 Inhibtor,” Molecular Cancer Therapy, Vol. 6, 2007, pp. 987-994. doi:10.1158/1535-7163.MCT-06-0605
[34] X. Y. Pei, Y. Dai and S. Grant, “The Proteasome Inhibitor Bortezomib Promotes Mitochondrial Injury and Apoptosis Induced by the Small Molecule Bcl-2 Inhibitor HA14-1 in Multiple Myeloma Cells,” Leukemia, Vol. 17, 2003, pp. 2036-2045. doi:10.1038/sj.leu.2403109
[35] S. Trudel, A. K. Stewart, Z. Li, Y. Shu, S. B. Liang, Y. Trieu, D. Reece, J. Paterson, D. Wang and X. Y. Wen, “The Bcl-2 Family Protein Inhibitor, ABT-737, Has Substantial Antimyeloma Activity and Shows Synergistic Effect with Dexamethasone and Melphalan,” Clinical Cancer Research, Vol. 13, 2007, pp. 621-629. doi:10.1158/1078-0432.CCR-06-1526
[36] M. Bhutani, A. K. Pathak, A. S. Nair, A. B. Kunnumakkara, S. Guha, G. Sethi and B. B. Aggarwal, “Capsaicin Is a Novel Blocker of Constitutive and Interleukin-6-Inducible STAT3 Activation,” Clinical Cancer Research, Vol. 13, 2007, pp. 3024-3032. doi:10.1158/1078-0432.CCR-06-2575
[37] J. Lotem and L. Sachs, “Regulation of bcl-2, bcl-XL and Bax in the Control of Apoptosis by Haemopoeitic Cytokines and Dexamethasone,” Cell Growth & Differentiation, Vol. 6, 1995, pp. 647-653.
[38] M. M. K. Schwarze and R. G. Hawley, “Prevention of Myeloma Cell Apoptosis by Ectopic bcl-2 Expression or Interleukin 6-Mediated Up-Regulation of bcl-xL,” Cancer Research, Vol. 55, No. 11, 1995, pp. 2262-2265.
[39] M. Yang, J. Huang, H. Z. Pan and J. Jin, “Triptolide Over-Comes Dexamethasone Resistance and Enhanced PS-341-Induced Apoptosis via PI3k/Akt/NF-kappaB Pathways in Human Multiple Myeloma Cells,” International Journal of Molecular Medicine, Vol. 22, No. 4, 2008, pp. 489-496.
[40] S. Greenstein, N. L. Krett, Y. Kurosawa, C. Ma, D. Chauhan, T. Hideshima, K. C. Anderson and S. T. Rosen, “Characterization of the MM.1 Human Multiple Myeloma (MM) Cell Lines: A Model System to Elucidate the Charactersistics, Behavior, and Signaling of Steroid-Sensitive and -Resistant MM Cells,” Experimental Hematology, Vol. 31, 2003, pp. 271-282. doi:10.1016/S0301-472X(03)00023-7
[41] K. D. Grugan, C. Ma, S. Singhal, N. L. Krett and S. T. Rosen, “Dual Regulation of Glucocorticoid-Induced Leucine Zipper (GILZ) by the Glucocorticoid Receptor and the PI3Kinase/AKT Pathways in Multiple Myeloma,” The Journal of Steroid Biochemistry and Molecular Biology, Vol. 110, No. 3-5, 2008, pp. 244-254. doi:10.1016/j.jsbmb.2007.11.003

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.