Skip to main content

Advertisement

SpringerLink
Log in

ABT-263 exhibits apoptosis-inducing potential in oral cancer cells by targeting C/EBP-homologous protein

  • Original Paper
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Purpose

ABT-263 is a potent BH3 mimetic that possesses anticancer potential against various types of cancer. In general, this potential is due to its high binding affinity to anti-apoptotic proteins in the Bcl-2 family that disrupt sequestration of pro-apoptotic proteins. In the present study, we sought to identify an alternative regulatory mechanism responsible for ABT-263-mediated anticancer activity in human oral cancer.

Methods

We investigated the in vitro anti-cancer effects of ABT-263 using a trypan blue exclusion assay, Western blotting, DAPI staining, immunofluorescence staining, a live/dead assay, microarray-based expression profiling, and quantitative real-time PCR. In vivo anti-tumorigenic effects of ABT-263 were examined using a nude mouse tumor xenograft model, a TUNEL assay, and immunohistochemistry.

Results

We found that ABT-263 suppressed viability and induced apoptosis in human oral cancer-derived cell lines HSC-3 and HSC-4. Subsequent microarray-based gene expression profiling revealed 55 differentially expressed genes in the ABT-263-treatead group, including 12 genes associated with “endoplasmic reticulum stress and apoptosis.” Consistent with the microarray results, the mRNA expression levels of the top four genes (CHOP, TRB3, ASNS, and STC2) were found to be significantly increased. In addition, we found that ABT-263 considerably enhanced the expression levels of the C/EBP-homologous protein (CHOP) and its mRNA, resulting in apoptosis induction in four other human oral cancer-derived cell lines (MC-3, YD-15, HN22, and Ca9.22). Extending our in vitro findings, we found that ABT-263 reduced the growth of HSC-4 cells in vivo at a dosage of 100 mg/kg/day without any change in body weight. TUNEL-positive cells were also found to be increased in tumors of ABT-263-treated mice without any apparent histopathological changes in liver or kidney tissues.

Conclusions

These results provide evidence that ABT-263 may serve as an effective therapeutic agent for the treatment of human oral cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. P.E. Czabotar, G. Lessene, A. Strasser, J.M. Adams, Control of apoptosis by the BCL-2 protein family: Implications for physiology and therapy. Nat Rev Mol Cell Biol 15, 49–63 (2014)

    Article  CAS  Google Scholar 

  2. T.N. Chonghaile, A. Letai, Mimicking the BH3 domain to kill cancer cells. Oncogene 27, S149–S157 (2008)

    Article  CAS  PubMed Central  Google Scholar 

  3. C. Bodur, H. Basaga, Bcl-2 inhibitors: Emerging drugs in cancer therapy. Curr Med Chem 19, 1804–1820 (2012)

    Article  CAS  PubMed  Google Scholar 

  4. A.C. Timucin, H. Basaga, O. Kutuk, Selective targeting of antiapoptotic BCL-2 proteins in cancer. Med Res Rev (2018)

  5. M. Bruncko, T.K. Oost, B.A. Belli, H. Ding, M.K. Joseph, A. Kunzer, D. Martineau, W.J. McClellan, M. Mitten, S.C. Ng, P.M. Nimmer, T. Oltersdorf, C.M. Park, A.M. Petros, A.R. Shoemaker, X. Song, X. Wang, M.D. Wendt, H. Zhang, S.W. Fesik, S.H. Rosenberg, S.W. Elmore, Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J Med Chem 50, 641–662 (2007)

    Article  CAS  PubMed  Google Scholar 

  6. T. Oltersdorf, S.W. Elmore, A.R. Shoemaker, R.C. Armstrong, D.J. Augeri, B.A. Belli, M. Bruncko, T.L. Deckwerth, J. Dinges, P.J. Hajduk, M.K. Joseph, S. Kitada, S.J. Korsmeyer, A.R. Kunzer, A. Letai, C. Li, M.J. Mitten, D.G. Nettesheim, S. Ng, P.M. Nimmer, J.M. O'Connor, A. Oleksijew, A.M. Petros, J.C. Reed, W. Shen, S.K. Tahir, C.B. Thompson, K.J. Tomaselli, B. Wang, M.D. Wendt, H. Zhang, S.W. Fesik, S.H. Rosenberg, An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677–681 (2005)

    Article  CAS  Google Scholar 

  7. J.A. Shin, L.H. Kim, S.J. Lee, J.H. Jeong, J.Y. Jung, H.N. Lee, I.S. Hong, S.D. Cho, Targeting ERK1/2-bim signaling cascades by BH3-mimetic ABT-737 as an alternative therapeutic strategy for oral cancer. Oncotarget 6, 35667–35683 (2015)

    PubMed  PubMed Central  Google Scholar 

  8. L.H. Kim, J.A. Shin, B. Jang, I.H. Yang, D.H. Won, J.H. Jeong, T.H. Chung, N.P. Cho, S.D. Cho, Sorafenib potentiates ABT-737-induced apoptosis in human oral cancer cells. Arch Oral Biol 73, 1–6 (2017)

    Article  CAS  PubMed  Google Scholar 

  9. L. Vela, I. Marzo, Bcl-2 family of proteins as drug targets for cancer chemotherapy: The long way of BH3 mimetics from bench to bedside. Curr Opin Pharmacol 23, 74–81 (2015)

    Article  CAS  PubMed  Google Scholar 

  10. C. Tse, A.R. Shoemaker, J. Adickes, M.G. Anderson, J. Chen, S. Jin, E.F. Johnson, K.C. Marsh, M.J. Mitten, P. Nimmer, L. Roberts, S.K. Tahir, Y. Xiao, X. Yang, H. Zhang, S. Fesik, S.H. Rosenberg, S.W. Elmore, ABT-263: A potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 68, 3421–3428 (2008)

    Article  CAS  Google Scholar 

  11. Q.H. Lin, F.C. Que, C.P. Gu, D.S. Zhong, D. Zhou, Y. Kong, L. Yu, S.W. Liu, ABT-263 induces G1/G0-phase arrest, apoptosis and autophagy in human esophageal cancer cells in vitro. Acta Pharmacol Sin 38, 1632–1641 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. A.R. Shoemaker, M.J. Mitten, J. Adickes, S. Ackler, M. Refici, D. Ferguson, A. Oleksijew, J.M. O'Connor, B. Wang, D.J. Frost, J. Bauch, K. Marsh, S.K. Tahir, X. Yang, C. Tse, S.W. Fesik, S.H. Rosenberg, S.W. Elmore, Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models. Clin Cancer Res 14, 3268–3277 (2008)

    Article  CAS  PubMed  Google Scholar 

  13. E. Szegezdi, S.E. Logue, A.M. Gorman, A. Samali, Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7, 880–885 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. E.Y. Lee, E.Y. Gong, J.S. Shin, J.H. Moon, H.J. Shim, S.M. Kim, S. Lee, J. Jeong, J.H. Gong, M.J. Kim, D.H. Lee, Y.S. Park, J. Shin, S.W. Hong, Y.S. Kim, D.H. Jin, Human breast cancer cells display different sensitivities to ABT-263 based on the level of survivin. Toxicol in Vitro 46, 229–236 (2018)

    Article  CAS  PubMed  Google Scholar 

  15. S. Suryani, H. Carol, T.N. Chonghaile, V. Frismantas, C. Sarmah, L. High, B. Bornhauser, M.J. Cowley, B. Szymanska, K. Evans, I. Boehm, E. Tonna, L. Jones, D.M. Manesh, R.T. Kurmasheva, C. Billups, W. Kaplan, A. Letai, J.P. Bourquin, P.J. Houghton, M.A. Smith, R.B. Lock, Cell and molecular determinants of in vivo efficacy of the BH3 mimetic ABT-263 against pediatric acute lymphoblastic leukemia xenografts. Clin Cancer Res 20, 4520–4531 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. C.D. Graham, N. Kaza, H.C. Pruitt, L.M. Gibson, B.J. Klocke, L.A. Shevde, S.L. Carroll, K.A. Roth, BH3 mimetics suppress CXCL12 expression in human malignant peripheral nerve sheath tumor cells. Oncotarget 8, 8670–8678 (2017)

    Article  PubMed  Google Scholar 

  17. G.X. Zhao, L.H. Xu, H. Pan, Q.R. Lin, M.Y. Huang, J.Y. Cai, D.Y. Ouyang, X.H. He, The BH3-mimetic gossypol and noncytotoxic doses of valproic acid induce apoptosis by suppressing cyclin-A2/Akt/FOXO3a signaling. Oncotarget 6, 38952–38966 (2015)

  18. I. Tabas, D. Ron, Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 13, 184–190 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. R.K. Yadav, S.W. Chae, H.R. Kim, H.J. Chae, Endoplasmic reticulum stress and cancer. J Cancer Prev 19, 75–88 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  20. W.A. Wang, J. Groenendyk, M. Michalak, Endoplasmic reticulum stress associated responses in cancer. Biochim Biophys Acta 1843, 2143–2149 (2014)

    Article  CAS  PubMed  Google Scholar 

  21. R. Soderquist, A.A. Pletnev, A.V. Danilov, A. Eastman, The putative BH3 mimetic S1 sensitizes leukemia to ABT-737 by increasing reactive oxygen species, inducing endoplasmic reticulum stress, and upregulating the BH3-only protein NOXA. Apoptosis 19, 201–209 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. R.S. Soderquist, A.V. Danilov, A. Eastman, Gossypol increases expression of the pro-apoptotic BH3-only protein NOXA through a novel mechanism involving phospholipase A2, cytoplasmic calcium, and endoplasmic reticulum stress. J Biol Chem 289, 16190–16199 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. N. Liu, Y. Xu, J.T. Sun, J. Su, X.Y. Xiang, H.W. Yi, Z.C. Zhang, L.K. Sun, The BH3 mimetic S1 induces endoplasmic reticulum stress-associated apoptosis in cisplatin-resistant human ovarian cancer cells although it activates autophagy. Oncol Rep 30, 2677–2684 (2013)

    Article  CAS  PubMed  Google Scholar 

  24. Y. Yang, L. Liu, I. Naik, Z. Braunstein, J. Zhong, B. Ren, Transcription factor C/EBP homologous protein in health and diseases. Front Immunol 8, 1612 (2017)

  25. S. Oyadomari, M. Mori, Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11, 381–389 (2004)

    Article  CAS  PubMed  Google Scholar 

  26. J. Tang, Y. Ge, L. Yang, X. Xu, T. Sui, D. Ge, J. Que, X. Cao, ER stress via CHOP pathway is involved in FK506-induced apoptosis in rat fibroblasts. Cell Physiol Biochem 39, 1965–1976 (2016)

    Article  CAS  PubMed  Google Scholar 

  27. Y. Lei, S. Wang, B. Ren, J. Wang, J. Chen, J. Lu, S. Zhan, Y. Fu, L. Huang, J. Tan, CHOP favors endoplasmic reticulum stress-induced apoptosis in hepatocellular carcinoma cells via inhibition of autophagy. PLoS One 12, e0183680 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. B. Sung, J. Ravindran, S. Prasad, M.K. Pandey, B.B. Aggarwal, Gossypol induces death receptor-5 through activation of the ROS-ERK-CHOP pathway and sensitizes colon cancer cells to TRAIL. J Biol Chem 285, 35418–35427 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science ICT & Future Planning [2017R1D1A1B03029124 and 2017R1A2B2003491].

Author information

Authors and Affiliations

  1. Department of Oral Pathology, School of Dentistry, Institute of Oral Bioscience, Chonbuk National University, Jeonju, 54896, Republic of Korea

    In-Hyoung Yang & Nam-Pyo Cho

  2. Department of Companion and Laboratory Animal Science, Kongju National University, Yesan, 32439, Republic of Korea

    Ji-Youn Jung, Sung-Hyun Kim & Eun-Seon Yoo

  3. Veterans Health Service Medical Center, Veterans Medical Research Institute, Seoul, 05368, Republic of Korea

    Hakmo Lee

  4. Department of Medicine, College of Medicine, Hanyang University, Seoul, 04763, Republic of Korea

    Jeong-Yeon Lee

  5. Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, 03080, Republic of Korea

    Seong Doo Hong, Ji-Ae Shin & Sung-Dae Cho

Authors
  1. In-Hyoung Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ji-Youn Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sung-Hyun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eun-Seon Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nam-Pyo Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hakmo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jeong-Yeon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Seong Doo Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ji-Ae Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sung-Dae Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ji-Ae Shin or Sung-Dae Cho.

Ethics declarations

Competing interests

The authors declare that they have no conflict of interest.

Ethical approval

All applicable institutional guidelines for the care and use of animals were followed.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, IH., Jung, JY., Kim, SH. et al. ABT-263 exhibits apoptosis-inducing potential in oral cancer cells by targeting C/EBP-homologous protein. Cell Oncol. 42, 357–368 (2019). https://doi.org/10.1007/s13402-019-00431-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-019-00431-5

Keywords

Search

Navigation