Display options
Cite
Sun S, Zhang Y, Zheng J, et al. HDAC6 inhibitor TST strengthens the antiproliferative effects of PI3K/mTOR inhibitor BEZ235 in breast cancer cells via suppressing RTK activation. Cell Death Dis. 2018;9(9):929doi: 10.1038/s41419-018-0931-0.
Sun, S., Zhang, Y., Zheng, J., Duan, B., Cui, J., Chen, Y., Deng, W., Ye, B., Liu, L., Chen, Y., Du, J., & Gu, L. (2018). HDAC6 inhibitor TST strengthens the antiproliferative effects of PI3K/mTOR inhibitor BEZ235 in breast cancer cells via suppressing RTK activation. Cell death & disease, 9(9), 929. https://doi.org/10.1038/s41419-018-0931-0
Sun, Shixiu, et al. "HDAC6 inhibitor TST strengthens the antiproliferative effects of PI3K/mTOR inhibitor BEZ235 in breast cancer cells via suppressing RTK activation." Cell death & disease vol. 9,9 (2018): 929. doi: https://doi.org/10.1038/s41419-018-0931-0
Sun S, Zhang Y, Zheng J, Duan B, Cui J, Chen Y, Deng W, Ye B, Liu L, Chen Y, Du J, Gu L. HDAC6 inhibitor TST strengthens the antiproliferative effects of PI3K/mTOR inhibitor BEZ235 in breast cancer cells via suppressing RTK activation. Cell Death Dis. 2018 Sep 11;9(9):929. doi: 10.1038/s41419-018-0931-0. PMID: 30206202; PMCID: PMC6134008.
Copy Download .nbib Format: NLM
Share it on

Cell Death Dis. 2018 Sep 11;9(9):929. doi: 10.1038/s41419-018-0931-0.

HDAC6 inhibitor TST strengthens the antiproliferative effects of PI3K/mTOR inhibitor BEZ235 in breast cancer cells via suppressing RTK activation.

Cell death & disease

Shixiu Sun, Yujie Zhang, Jianchao Zheng, Biao Duan, Jie Cui, Yan Chen, Wenjie Deng, Bixing Ye, Lei Liu, Yongchang Chen, Jun Du, Luo Gu

Affiliations

  1. Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
  2. Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
  3. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
  4. BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, Guangdong, 518083, China.
  5. Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
  6. Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
  7. Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
  8. Department of Physiology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
  9. Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. [email protected].
  10. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. [email protected].
  11. Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. [email protected].
  12. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. [email protected].
  13. Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. [email protected].

PMID: 30206202 PMCID: PMC6134008 DOI: 10.1038/s41419-018-0931-0

Abstract

NVP-BEZ235 (BEZ235), an available dual PI3K/mTOR inhibitor, showed antitumor effect and provided a therapy strategy in carcinomas. However, the acquired upregulation of multiple receptor tyrosine kinases (RTKs) by NVP-BEZ235 in tumors limits its clinical efficacy. HDAC6, a class II histone deacetylase, is associated with expressions of multiple RTKs. The aim of this study was to detect whether co-treatment with HDAC6 inhibitor Tubastatin A (TST) would enhance the anticancer effects of BEZ235 in breast cancer cells. In this study, we described that treatment of breast cancer cell lines (T47D, BT474, and MDA-MB-468) with BEZ235 significantly triggered PI3K/mTOR signaling inactivation and increased multiple RTK expression, including EGFR, HER2, HER3, IGF-1 receptor, insulin receptor, and their phosphorylation levels. The adding of TST destabilized these RTKs in those breast cancer cells. Co-treatment with BEZ235 and TST reduced cell proliferative rate by strengthening Akt inactivation. In addition, the combination of these two drugs also cooperatively arrested cell cycle and DNA synthesis. In conclusion, the co-treatment with PI3K/mTOR inhibitor BEZ235 and HDAC6 inhibitor TST displayed additive antiproliferative effects on breast cancer cells through inactivating RTKs and established a rationable combination therapy to treat breast cancer.

References

  1. Dodwell, D. & Williamson, D. Beyond tamoxifen: extended and late extended endocrine therapy in postmenopausal early breast cancer. Cancer Treat. Rev. 34, 137–144 (2008). - PubMed
  2. Wang, X. Y. et al. Musashi1 regulates breast tumor cell proliferation and is a prognostic indicator of poor survival. Mol. Cancer 9, 221 (2010). - PubMed
  3. Sanchez-Munoz, A. et al. Targeted therapy of metastatic breast cancer. Clin. Transl. Oncol. 11, 643–650 (2009). - PubMed
  4. Yuan, T. L. & Cantley, L. C. PI3K pathway alterations in cancer: variations on a theme. Oncogene 27, 5497–5510 (2008). - PubMed
  5. Niederst, M. J. & Engelman, J. A. Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer. Sci. Signal. 6, re6 (2013). - PubMed
  6. Chandarlapaty, S. et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 19, 58–71 (2011). - PubMed
  7. Serra, V. et al. PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene 30, 2547–2557 (2011). - PubMed
  8. Chakrabarty, A., Sanchez, V., Kuba, M. G., Rinehart, C. & Arteaga, C. L. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc. Natl Acad. Sci. USA 109, 2718–2723 (2012). - PubMed
  9. Serra, V. et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 68, 8022–8030 (2008). - PubMed
  10. Cao, P., Maira, S. M., Garcia-Echeverria, C. & Hedley, D. W. Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts. Br. J. Cancer 100, 1267–1276 (2009). - PubMed
  11. Baumann, P., Mandl-Weber, S., Oduncu, F. & Schmidmaier, R. The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma. Exp. Cell Res. 315, 485–497 (2009). - PubMed
  12. Muranen, T. et al. Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells. Cancer Cell 21, 227–239 (2012). - PubMed
  13. Sahin, O. et al. Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors. Cell Res. 24, 542–559 (2014). - PubMed
  14. Wong, M. H., Xue, A., Baxter, R. C., Pavlakis, N. & Smith, R. C. Upstream and downstream co-inhibition of mitogen-activated protein kinase and PI3K/Akt/mTOR pathways in pancreatic ductal adenocarcinoma. Neoplasia 18, 425–435 (2016). - PubMed
  15. Aldana-Masangkay, G. I. & Sakamoto, K. M. The role of HDAC6 in cancer. J. Biomed. Biotechnol. 2011, 875824 (2011). - PubMed
  16. Bali, P. et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J. Biol. Chem. 280, 26729–26734 (2005). - PubMed
  17. Sawai, A. et al. Inhibition of Hsp90 down-regulates mutant epidermal growth factor receptor (EGFR) expression and sensitizes EGFR mutant tumors to paclitaxel. Cancer Res. 68, 589–596 (2008). - PubMed
  18. Berezowska, S. et al. Association between HSP90 and Her2 in gastric and gastroesophageal carcinomas. PLoS ONE 8, e69098 (2013). - PubMed
  19. Jiao, Y., Ou, W., Meng, F., Zhou, H. & Wang, A. Targeting HSP90 in ovarian cancers with multiple receptor tyrosine kinase coactivation. Mol. Cancer 10, 125 (2011). - PubMed
  20. Soares, H. P. et al. Dual PI3K/mTOR inhibitors induce rapid overactivation of the MEK/ERK pathway in human pancreatic cancer cells through suppression of mTORC2. Mol. Cancer Ther. 14, 1014–1023 (2015). - PubMed
  21. Rodrik-Outmezguine, V. S. et al. mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov. 1, 248–259 (2011). - PubMed
  22. Keniry, M. & Parsons, R. mTOR inhibition, the second generation: ATP-competitive mTOR inhibitor initiates unexpected receptor tyrosine kinase-driven feedback loop. Cancer Discov. 1, 203–204 (2011). - PubMed
  23. Chen, S. M. et al. HSP90 inhibitor AUY922 abrogates up-regulation of RTKs by mTOR inhibitor AZD8055 and potentiates its antiproliferative activity in human breast cancer. Int. J. Cancer 135, 2462–2474 (2014). - PubMed
  24. Koutras, A. K. et al. The upgraded role of HER3 and HER4 receptors in breast cancer. Crit. Rev. Oncol. Hematol. 74, 73–78 (2010). - PubMed
  25. Yang, P. HDAC6: Physiological function and its selective inhibitors for cancer treatment. Drug Discov. Ther. 7, 233–242 (2013). - PubMed
  26. Czeisler, C. & Mikawa, T. Microtubules coordinate VEGFR2 signaling and sorting. PLoS ONE 8, e75833 (2013). - PubMed
  27. Park, S. J. et al. HDAC6 sustains growth stimulation by prolonging the activation of EGF receptor through the inhibition of rabaptin-5-mediated early endosome fusion in gastric cancer. Cancer Lett. 354, 97–106 (2014). - PubMed
  28. Gravina, G. L. et al. PXD101 potentiates hormonal therapy and prevents the onset of castration-resistant phenotype modulating androgen receptor, HSP90, and CRM1 in preclinical models of prostate cancer. Endocr. Relat. Cancer 20, 321–337 (2013). - PubMed
  29. Deribe, Y. L. et al. Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6. Sci. Signal. 2, ra84 (2009). - PubMed
  30. Seo, J. et al. Expression of histone deacetylases HDAC1, HDAC2, HDAC3, and HDAC6 in invasive ductal carcinomas of the breast. J. Breast Cancer 17, 323–331 (2014). - PubMed
  31. Meng, Q. et al. Carbamazepine promotes Her-2 protein degradation in breast cancer cells by modulating HDAC6 activity and acetylation of Hsp90. Mol. Cell. Biochem. 348, 165–171 (2011). - PubMed
  32. Jin, Z. J. et al. Addition in drug combination (author’s transl). Zhongguo Yao Li Xue Bao 1, 70–76 (1980). - PubMed
  33. Yang, S. X., Polley, E. & Lipkowitz, S. New insights on PI3K/AKT pathway alterations and clinical outcomes in breast cancer. Cancer Treat. Rev. 45, 87–96 (2016). - PubMed
  34. Fox, E. M., Kuba, M. G., Miller, T. W., Davies, B. R. & Arteaga, C. L. Autocrine IGF-I/insulin receptor axis compensates for inhibition of AKT in ER-positive breast cancer cells with resistance to estrogen deprivation. Breast Cancer Res. 15, R55 (2013). - PubMed
  35. Kramer, O. H., Mahboobi, S. & Sellmer, A. Drugging the HDAC6-HSP90 interplay in malignant cells. Trends Pharmacol. Sci. 35, 501–509 (2014). - PubMed
  36. Scott, G. K. et al. Destabilization of ERBB2 transcripts by targeting 3’ untranslated region messenger RNA associated HuR and histone deacetylase-6. Mol. Cancer Res. 6, 1250–1258 (2008). - PubMed
  37. Deribe YL, W. P. et al. Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6. Sci. Signal. 2, ra84 (2009). - PubMed
  38. Meng, Z., Jia, L. F. & Gan, Y. H. PTEN activation through K163 acetylation by inhibiting HDAC6 contributes to tumour inhibition. Oncogene 35, 2333–2344 (2016). - PubMed
  39. Gradilone, S. A. et al. HDAC6 inhibition restores ciliary expression and decreases tumor growth. Cancer Res. 73, 2259–2270 (2013). - PubMed
  40. Duan, B. et al. EGF-stimulated activation of Rab35 regulates RUSC2-GIT2 complex formation to stabilize GIT2 during directional lung cancer cell migration. Cancer Lett. 379, 70–83 (2016). - PubMed
  41. Zhang, Y. et al. EGF-reduced Wnt5a transcription induces epithelial-mesenchymal transition via Arf6-ERK signaling in gastric cancer cells. Oncotarget 6, 7244–7261 (2015). - PubMed

Publication Types