DOI QR코드

DOI QR Code

Lysophosphatidic acid enhances breast cancer cells-mediated osteoclastogenesis

  • Nam, Ju-Suk (Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital) ;
  • Sharma, Ashish Ranjan (Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital) ;
  • Nguyen, Lich Thi (Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital) ;
  • Jagga, Supriya (Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital) ;
  • Lee, Yeon-Hee (Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital) ;
  • Sharma, Garima (Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital) ;
  • Lee, Sang-Soo (Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital)
  • 투고 : 2018.01.21
  • 심사 : 2018.05.18
  • 발행 : 2018.09.01

초록

Lysophosphatidic acid (LPA) is known to play a critical role in breast cancer metastasis to bone. In this study, we tried to investigate any role of LPA in the regulation of osteoclastogenic cytokines from breast cancer cells and the possibility of these secretory factors in affecting osteoclastogenesis. Effect of secreted cytokines on osteoclastogenesis was analyzed by treating conditioned media from LPA-stimulated breast cancer cells to differentiating osteoclasts. Result demonstrated that IL-8 and IL-11 expression were upregulated in LPA-treated MDA-MB-231 cells. IL-8 was induced in both MDA-MB-231 and MDA-MB-468, however, IL-11 was induced only in MDA-MB-231, suggesting differential LPARs participation in the expression of these cytokines. Expression of IL-8 but not IL-11 was suppressed by inhibitors of PI3K, NF-kB, ROCK and PKC pathways. In the case of PKC activation, it was observed that $PKC{\delta}$ and $PKC{\mu}$ might regulate LPA-induced expression of IL-11 and IL-8, respectively, by using specific PKC subtype inhibitors. Finally, conditioned Medium from LPA-stimulated breast cancer cells induced osteoclastogenesis. In conclusion, LPA induced the expression of osteolytic cytokines (IL-8 and IL-11) in breast cancer cells by involving different LPA receptors. Enhanced expression of IL-8 by LPA may be via ROCK, PKCu, PI3K, and NFkB signaling pathways, while enhanced expression of IL-11 might involve $PKC{\delta}$ signaling pathway. LPA has the ability to enhance breast cancer cells-mediated osteoclastogenesis by inducing the secretion of cytokines such as IL-8 and IL-11.

키워드

참고문헌

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87-108. https://doi.org/10.3322/caac.21262
  2. Lin Y, Huang R, Chen L, Li S, Shi Q, Jordan C, Huang RP. Identification of interleukin-8 as estrogen receptor-regulated factor involved in breast cancer invasion and angiogenesis by protein arrays. Int J Cancer. 2004;109:507-515. https://doi.org/10.1002/ijc.11724
  3. Yao C, Lin Y, Chua MS, Ye CS, Bi J, Li W, Zhu YF, Wang SM. Interleukin-8 modulates growth and invasiveness of estrogen receptornegative breast cancer cells. Int J Cancer. 2007;121:1949-1957. https://doi.org/10.1002/ijc.22930
  4. Li A, Dubey S, Varney ML, Dave BJ, Singh RK. IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol. 2003;170:3369-3376. https://doi.org/10.4049/jimmunol.170.6.3369
  5. Martin D, Galisteo R, Gutkind JS. CXCL8/IL8 stimulates vascular endothelial growth factor (VEGF) expression and the autocrine activation of VEGFR2 in endothelial cells by activating NFkappaB through the CBM (Carma3/Bcl10/Malt1) complex. J Biol Chem. 2009;284:6038-6042. https://doi.org/10.1074/jbc.C800207200
  6. Marusyk A, Tabassum DP, Altrock PM, Almendro V, Michor F, Polyak K. Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. Nature. 2014;514:54-58. https://doi.org/10.1038/nature13556
  7. Benoy IH, Salgado R, Van Dam P, Geboers K, Van Marck E, Scharpe S, Vermeulen PB, Dirix LY. Increased serum interleukin-8 in patients with early and metastatic breast cancer correlates with early dissemination and survival. Clin Cancer Res. 2004;10:7157-7162. https://doi.org/10.1158/1078-0432.CCR-04-0812
  8. Sotiriou C, Lacroix M, Lespagnard L, Larsimont D, Paesmans M, Body JJ. Interleukins-6 and -11 expression in primary breast cancer and subsequent development of bone metastases. Cancer Lett. 2001;169:87-95. https://doi.org/10.1016/S0304-3835(01)00524-9
  9. Morgan H, Tumber A, Hill PA. Breast cancer cells induce osteoclast formation by stimulating host IL-11 production and downregulating granulocyte/macrophage colony-stimulating factor. Int J Cancer. 2004;109:653-660. https://doi.org/10.1002/ijc.20056
  10. McCoy EM, Hong H, Pruitt HC, Feng X. IL-11 produced by breast cancer cells augments osteoclastogenesis by sustaining the pool of osteoclast progenitor cells. BMC Cancer. 2013;13:16. https://doi.org/10.1186/1471-2407-13-16
  11. Bendre MS, Montague DC, Peery T, Akel NS, Gaddy D, Suva LJ. Interleukin-8 stimulation of osteoclastogenesis and bone resorption is a mechanism for the increased osteolysis of metastatic bone disease. Bone. 2003;33:28-37. https://doi.org/10.1016/S8756-3282(03)00086-3
  12. Boucharaba A, Serre CM, Guglielmi J, Bordet JC, Clezardin P, Peyruchaud O. The type 1 lysophosphatidic acid receptor is a target for therapy in bone metastases. Proc Natl Acad Sci U S A. 2006;103:9643-9648. https://doi.org/10.1073/pnas.0600979103
  13. Mills GB, Moolenaar WH. The emerging role of lysophosphatidic acid in cancer. Nat Rev Cancer. 2003;3:582-591. https://doi.org/10.1038/nrc1143
  14. Chen M, Towers LN, O'Connor KL. LPA2 (EDG4) mediates Rho-dependent chemotaxis with lower efficacy than LPA1 (EDG2) in breast carcinoma cells. Am J Physiol Cell Physiol. 2007;292:C1927-1933. https://doi.org/10.1152/ajpcell.00400.2006
  15. Liu S, Umezu-Goto M, Murph M, Lu Y, Liu W, Zhang F, Yu S, Stephens LC, Cui X, Murrow G, Coombes K, Muller W, Hung MC, Perou CM, Lee AV, Fang X, Mills GB. Expression of autotaxin and lysophosphatidic acid receptors increases mammary tumorigenesis, invasion, and metastases. Cancer Cell. 2009;15:539-550. https://doi.org/10.1016/j.ccr.2009.03.027
  16. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434:843-850. https://doi.org/10.1038/nature03319
  17. Li Y, Welm B, Podsypanina K, Huang S, Chamorro M, Zhang X, Rowlands T, Egeblad M, Cowin P, Werb Z, Tan LK, Rosen JM, Varmus HE. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci U S A. 2003;100:15853-15858. https://doi.org/10.1073/pnas.2136825100
  18. Liu S, Murph M, Panupinthu N, Mills GB. ATX-LPA receptor axis in inflammation and cancer. Cell Cycle. 2009;8:3695-3701. https://doi.org/10.4161/cc.8.22.9937
  19. Panupinthu N, Lee HY, Mills GB. Lysophosphatidic acid production and action: critical new players in breast cancer initiation and progression. Br J Cancer. 2010;102:941-946. https://doi.org/10.1038/sj.bjc.6605588
  20. Boucharaba A, Serre CM, Gres S, Saulnier-Blache JS, Bordet JC, Guglielmi J, Clezardin P, Peyruchaud O. Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer. J Clin Invest. 2004;114:1714-1725. https://doi.org/10.1172/JCI200422123
  21. Du J, Sun C, Hu Z, Yang Y, Zhu Y, Zheng D, Gu L, Lu X. Lysophosphatidic acid induces MDA-MB-231 breast cancer cells migration through activation of PI3K/PAK1/ERK signaling. PLoS One. 2010;5:e15940. https://doi.org/10.1371/journal.pone.0015940
  22. Samadi N, Bekele RT, Goping IS, Schang LM, Brindley DN. Lysophosphatidate induces chemo-resistance by releasing breast cancer cells from taxol-induced mitotic arrest. PLoS One. 2011;6:e20608. https://doi.org/10.1371/journal.pone.0020608
  23. Hama K, Aoki J, Fukaya M, Kishi Y, Sakai T, Suzuki R, Ohta H, Yamori T, Watanabe M, Chun J, Arai H. Lysophosphatidic acid and autotaxin stimulate cell motility of neoplastic and non-neoplastic cells through LPA1. J Biol Chem. 2004;279:17634-17639. https://doi.org/10.1074/jbc.M313927200
  24. Swamydas M, Nguyen D, Allen LD, Eddy J, Dreau D. Progranulin stimulated by LPA promotes the migration of aggressive breast cancer cells. Cell Commun Adhes. 2011;18:119-130. https://doi.org/10.3109/15419061.2011.641042
  25. Brunner N, Boysen B, Romer J, Spang-Thomsen M. The nude mouse as an in vivo model for human breast cancer invasion and metastasis. Breast Cancer Res Treat. 1993;24:257-264. https://doi.org/10.1007/BF01833265
  26. Chekhun S, Bezdenezhnykh N, Shvets J, Lukianova N. Expression of biomarkers related to cell adhesion, metastasis and invasion of breast cancer cell lines of different molecular subtype. Exp Oncol. 2013;35:174-179.
  27. Dickson RB, Bates SE, McManaway ME, Lippman ME. Characterization of estrogen responsive transforming activity in human breast cancer cell lines. Cancer Res. 1986;46:1707-1713.
  28. Hwang YS, Lee SK, Park KK, Chung WY. Secretion of IL-6 and IL-8 from lysophosphatidic acid-stimulated oral squamous cell carcinoma promotes osteoclastogenesis and bone resorption. Oral Oncol. 2012;48:40-48. https://doi.org/10.1016/j.oraloncology.2011.08.022
  29. Shimada H, Rajagopalan LE. Rho-kinase mediates lysophosphatidic acid-induced IL-8 and MCP-1 production via p38 and JNK pathways in human endothelial cells. FEBS Lett. 2010;584:2827-2832. https://doi.org/10.1016/j.febslet.2010.04.064
  30. Hartman ZC, Poage GM, den Hollander P, Tsimelzon A, Hill J, Panupinthu N, Zhang Y, Mazumdar A, Hilsenbeck SG, Mills GB, Brown PH. Growth of triple-negative breast cancer cells relies upon coordinate autocrine expression of the proinflammatory cytokines IL-6 and IL-8. Cancer Res. 2013;73:3470-3480. https://doi.org/10.1158/0008-5472.CAN-12-4524-T
  31. Chen RJ, Chen SU, Chou CH, Lin MC. Lysophosphatidic acid receptor 2/3-mediated IL-8-dependent angiogenesis in cervical cancer cells. Int J Cancer. 2012;131:789-802. https://doi.org/10.1002/ijc.26476
  32. Gupta J, Robbins J, Jilling T, Seth P. $TGF{\beta}$-dependent induction of interleukin-11 and interleukin-8 involves SMAD and p38 MAPK pathways in breast tumor models with varied bone metastases potential. Cancer Biol Ther. 2011;11:311-316. https://doi.org/10.4161/cbt.11.3.14096
  33. Matsumoto T, Kuriwaka-Kido R, Kondo T, Endo I, Kido S. Regulation of osteoblast differentiation by interleukin-11 via AP-1 and Smad signaling. Endocr J. 2012;59:91-101. https://doi.org/10.1507/endocrj.EJ11-0219
  34. Kido S, Kuriwaka-Kido R, Umino-Miyatani Y, Endo I, Inoue D, Taniguchi H, Inoue Y, Imamura T, Matsumoto T. Mechanical stress activates Smad pathway through $PKC{\delta}$ to enhance interleukin-11 gene transcription in osteoblasts. PLoS One. 2010;5:e13090. https://doi.org/10.1371/journal.pone.0013090
  35. Brenner W, Beitz S, Schneider E, Benzing F, Unger RE, Roos FC, Thuroff JW, Hampel C. Adhesion of renal carcinoma cells to endothelial cells depends on PKCmu. BMC Cancer. 2010;10:183. https://doi.org/10.1186/1471-2407-10-183
  36. David M, Wannecq E, Descotes F, Jansen S, Deux B, Ribeiro J, Serre CM, Gres S, Bendriss-Vermare N, Bollen M, Saez S, Aoki J, Saulnier-Blache JS, Clezardin P, Peyruchaud O. Cancer cell expression of autotaxin controls bone metastasis formation in mouse through lysophosphatidic acid-dependent activation of osteoclasts. PLoS One. 2010;5:e9741. https://doi.org/10.1371/journal.pone.0009741
  37. Kang Y, He W, Tulley S, Gupta GP, Serganova I, Chen CR, Manova-Todorova K, Blasberg R, Gerald WL, Massague J. Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc Natl Acad Sci U S A. 2005;102:13909-13914. https://doi.org/10.1073/pnas.0506517102
  38. Mu H, Calderone TL, Davies MA, Prieto VG, Wang H, Mills GB, Bar-Eli M, Gershenwald JE. Lysophosphatidic acid induces lymphangiogenesis and IL-8 production in vitro in human lymphatic endothelial cells. Am J Pathol. 2012;180:2170-2181. https://doi.org/10.1016/j.ajpath.2012.03.003
  39. Yung YC, Stoddard NC, Chun J. LPA receptor signaling: pharmacology, physiology, and pathophysiology. J Lipid Res. 2014;55:1192-1214. https://doi.org/10.1194/jlr.R046458
  40. Tigyi G. Aiming drug discovery at lysophosphatidic acid targets. Br J Pharmacol. 2010;161:241-270. https://doi.org/10.1111/j.1476-5381.2010.00815.x
  41. Morse-Gaudio M, Connolly JM, Rose DP. Protein kinase C and its isoforms in human breast cancer cells: relationship to the invasive phenotype. Int J Oncol. 1998;12:1349-1354.

피인용 문헌

  1. What Is the Role of Interleukins in Breast Cancer Bone Metastases? A Systematic Review of Preclinical and Clinical Evidence vol.11, pp.12, 2018, https://doi.org/10.3390/cancers11122018
  2. Interleukin 11 (IL-11): Role(s) in Breast Cancer Bone Metastases vol.9, pp.6, 2021, https://doi.org/10.3390/biomedicines9060659
  3. Lysophosphatidic Acid Signaling in Cancer Cells: What Makes LPA So Special? vol.10, pp.8, 2018, https://doi.org/10.3390/cells10082059