DOI QR코드

DOI QR Code

Chloroquine Exerts Anti-metastatic Activities Under Hypoxic Conditions in Cholangiocarcinoma Cells

  • 발행 : 2015.03.18

초록

Intra-tumoral hypoxia is an environment that promotes tumor cell migration, angiogenesis and epithelial-mesenchymal transition that accounts for a major mechanism of metastasis. Chloroquine potentially offers a new therapeutic approach with an 'old' drug for effective and safe cancer therapies, as it exerts anti-metastatic activity. We investigated the inhibitory effect of chloroquine on cholangiocarcinoma (CCA) cell migration under cobalt chloride ($CoCl_2$)-stimulated hypoxia. We showed that chloroquine suppressed CCA cell migration under hypoxic-mimicking conditions on exposure to $100{\mu}M$ $CoCl_2$. Moreover, chloroquine stabilized the protein level of prolyl hydroxylase domain proteins (PHD-2) but reduced the levels of hypoxic responsive proteins such as hypoxia-inducible factor (HIF-$1{\alpha}$) and vascular endothelial growth factor (VEGF). It also suppressed epithelial mesenchymal transition (EMT) by increasing the ratio of E-cadherin to N-cadherin under hypoxic conditions. In conclusion, chloroquine can inhibit hypoxia-stimulated metastasis via HIF-$1{\alpha}$/VEGF/EMT which may serve as a useful additional strategy for CCA therapy.

키워드

참고문헌

  1. Blechacz B, Gores GJ (2008). Cholangiocarcinoma: advances in pathogenesis, diagnosis, and treatment. Hepatology, 48, 308-21.
  2. Chen J, Zhao J, Ma R, et al (2014). Prognostic significance of E-cadherin expression in hepatocellular carcinoma: a metaanalysis. PloS One, 9, 103952. https://doi.org/10.1371/journal.pone.0103952
  3. Fan C, Wang W, Zhao B, et al (2006). Chloroquine inhibits cell growth and induces cell death in A549 lung cancer cells. Bioorg Med Chem, 14, 3218-22. https://doi.org/10.1016/j.bmc.2005.12.035
  4. Fan L, Li J, Yu Z, et al (2014). The hypoxia-inducible factor pathway, prolyl hydroxylase domain protein inhibitors, and their roles in bone repair and regeneration. Biomed Res Int, 2014, 239356.
  5. Gravdal K, Halvorsen OJ, Haukaas SA, et al (2007). A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin Cancer Res, 13, 7003-11. https://doi.org/10.1158/1078-0432.CCR-07-1263
  6. Jiang P-D, Zhao Y-L, Deng X-Q, et al (2010). Antitumor and antimetastatic activities of chloroquine diphosphate in a murine model of breast cancer. Biomed Pharmacother, 64, 609-14. https://doi.org/10.1016/j.biopha.2010.06.004
  7. Law P-C, Auyeung KK, Chan L-Y, et al (2012). Astragalus saponins downregulate vascular endothelial growth factor under cobalt chloride-stimulated hypoxia in colon cancer cells. BMC Complement Altern Med, 12, 160. https://doi.org/10.1186/1472-6882-12-160
  8. Liu L, Ning X, Sun L, et al (2008). Hypoxia-inducible factor-$1\alpha$ contributes to hypoxia-induced chemoresistance in gastric cancer. Cancer Sci, 99, 121-8.
  9. Liu X-H, Kirschenbaum A, Yao S, et al (1999). Upregulation of vascular endothelial growth factor by cobalt chloridesimulated hypoxia is mediated by persistent induction of cyclooxygenase-2 in a metastatic human prostate cancer cell line. Clin Exp Metastasis, 17, 687-94. https://doi.org/10.1023/A:1006728119549
  10. O'Donnell JL, Joyce MR, Shannon AM, et al (2006). Oncological implications of hypoxia inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$) expression. Cancer Treat Rev, 32, 407-16. https://doi.org/10.1016/j.ctrv.2006.05.003
  11. Sahlgren C, Gustafsson MV, Jin S, et al (2008). Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA, 105, 6392-7. https://doi.org/10.1073/pnas.0802047105
  12. Salnikov AV, Liu L, Platen M, et al (2012). Hypoxia induces EMT in low and highly aggressive pancreatic tumor cells but only cells with cancer stem cell characteristics acquire pronounced migratory potential. PloS One, 7, 46391. https://doi.org/10.1371/journal.pone.0046391
  13. Semenza GL (2012). Molecular mechanisms mediating metastasis of hypoxic breast cancer cells. Trends Mol Med, 18, 534-43. https://doi.org/10.1016/j.molmed.2012.08.001
  14. Seubwai W, Kraiklang R, Wongkham C, et al (2012). Hypoxia enhances aggressiveness of cholangiocarcinoma cells. Asian Pac J Cancer Prev, 13, 53-8.
  15. Songserm N, Prasongwattana J, Sithithaworn P, et al (2009). Cholangiocarcinoma in experimental hamsters with longstanding Opisthorchis viverrini infection. Asian Pac J Cancer Prev, 10, 299-302.
  16. Sripa B, Bethony JM, Sithithaworn P, et al (2011). Opisthorchiasis and Opisthorchis-associated cholangiocarcinoma in Thailand and Laos. Acta Trop, 120, 158-68. https://doi.org/10.1016/j.actatropica.2010.07.006
  17. Thongchot S, Yongvanit P, Loilome W, et al (2014). High Expression of HIF-$1{\alpha}$, BNIP3 and PI3KC3: hypoxiainduced autophagy predicts cholangiocarcinoma survival and metastasis. Asian Pac J Cancer Prev, 15, 5873-8. https://doi.org/10.7314/APJCP.2014.15.14.5873
  18. Thongprasert S (2005). The role of chemotherapy in cholangiocarcinoma. Ann Oncol, 16, 93-6.
  19. Tuomela J, Sandholm J, Kauppila JH, et al (2013). Chloroquine has tumor-inhibitory and tumor-promoting effects in triple-negative breast cancer. Oncol Lett, 6, 1665-72.
  20. Vaupel P, Mayer A (2007). Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev, 26, 225-39. https://doi.org/10.1007/s10555-007-9055-1
  21. Winstanley P (2003). The contribution of clinical pharmacology to antimalarial drug discovery and development. Br J Clin Pharmacol, 55, 464-8. https://doi.org/10.1046/j.1365-2125.2003.01845.x
  22. Wu D, Yotnda P (2011). Induction and testing of hypoxia in cell culture. J Vis Exp, 12, 2899.
  23. Yang Z, Zhang X, Gang H, et al (2007). Up-regulation of gastric cancer cell invasion by Twist is accompanied by N-cadherin and fibronectin expression. Biochem Biophys Res Commun, 358, 925-30. https://doi.org/10.1016/j.bbrc.2007.05.023
  24. Yuan Y, Hilliard G, Ferguson T, et al (2003). Cobalt inhibits the interaction between hypoxia-inducible factor-alpha and von hippel-lindau protein by direct binding to hypoxia-inducible factor-alpha. J Biol Chem, 278, 15911-6. https://doi.org/10.1074/jbc.M300463200
  25. Zhang L, Huang G, Li X, et al (2013). Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor-$1{\alpha}$ in hepatocellular carcinoma. BMC Cancer, 13, 108. https://doi.org/10.1186/1471-2407-13-108

피인용 문헌

  1. Establishment of cholangiocarcinoma cell lines from patients in the endemic area of liver fluke infection in Thailand vol.39, pp.11, 2017, https://doi.org/10.1177/1010428317725925