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

In Hyoung Yang, Ji Youn Jung, Sung Hyun Kim, Eun Seon Yoo, Nam Pyo Cho, Hakmo Lee, Jeong-Yeon Lee, Seong Doo Hong, Ji Ae Shin, Sung Dae Cho

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)357-368
Number of pages12
JournalCellular oncology (Dordrecht)
Volume42
Issue number3
DOIs
StatePublished - 2019 Jun 1

Fingerprint

Transcription Factor CHOP
Mouth Neoplasms
Apoptosis
Apoptosis Regulatory Proteins
In Situ Nick-End Labeling
Neoplasms
navitoclax
Staining and Labeling
Genes
Cell Line
Messenger RNA
Body Weight Changes
Endoplasmic Reticulum Stress
Trypan Blue
Gene Expression Profiling
Heterografts
Nude Mice
Human Activities
Fluorescent Antibody Technique
Real-Time Polymerase Chain Reaction

Keywords

  • ABT-263
  • Apoptosis
  • CHOP
  • ER stress
  • Oral cancer

Cite this

Yang, In Hyoung ; Jung, Ji Youn ; Kim, Sung Hyun ; Yoo, Eun Seon ; Cho, Nam Pyo ; Lee, Hakmo ; Lee, Jeong-Yeon ; Hong, Seong Doo ; Shin, Ji Ae ; Cho, Sung Dae. / ABT-263 exhibits apoptosis-inducing potential in oral cancer cells by targeting C/EBP-homologous protein. In: Cellular oncology (Dordrecht). 2019 ; Vol. 42, No. 3. pp. 357-368.
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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.",
keywords = "ABT-263, Apoptosis, CHOP, ER stress, Oral cancer",
author = "Yang, {In Hyoung} and Jung, {Ji Youn} and Kim, {Sung Hyun} and Yoo, {Eun Seon} and Cho, {Nam Pyo} and Hakmo Lee and Jeong-Yeon Lee and Hong, {Seong Doo} and Shin, {Ji Ae} and Cho, {Sung Dae}",
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Yang, IH, Jung, JY, Kim, SH, Yoo, ES, Cho, NP, Lee, H, Lee, J-Y, Hong, SD, Shin, JA & Cho, SD 2019, 'ABT-263 exhibits apoptosis-inducing potential in oral cancer cells by targeting C/EBP-homologous protein', Cellular oncology (Dordrecht), vol. 42, no. 3, pp. 357-368. https://doi.org/10.1007/s13402-019-00431-5

ABT-263 exhibits apoptosis-inducing potential in oral cancer cells by targeting C/EBP-homologous protein. / Yang, In Hyoung; Jung, Ji Youn; Kim, Sung Hyun; Yoo, Eun Seon; Cho, Nam Pyo; Lee, Hakmo; Lee, Jeong-Yeon; Hong, Seong Doo; Shin, Ji Ae; Cho, Sung Dae.

In: Cellular oncology (Dordrecht), Vol. 42, No. 3, 01.06.2019, p. 357-368.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - ABT-263 exhibits apoptosis-inducing potential in oral cancer cells by targeting C/EBP-homologous protein

AU - Yang, In Hyoung

AU - Jung, Ji Youn

AU - Kim, Sung Hyun

AU - Yoo, Eun Seon

AU - Cho, Nam Pyo

AU - Lee, Hakmo

AU - Lee, Jeong-Yeon

AU - Hong, Seong Doo

AU - Shin, Ji Ae

AU - Cho, Sung Dae

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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.

AB - 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.

KW - ABT-263

KW - Apoptosis

KW - CHOP

KW - ER stress

KW - Oral cancer

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U2 - 10.1007/s13402-019-00431-5

DO - 10.1007/s13402-019-00431-5

M3 - Article

VL - 42

SP - 357

EP - 368

JO - Cellular oncology (Dordrecht)

JF - Cellular oncology (Dordrecht)

SN - 2211-3436

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