Berberine induces FasL-related apoptosis through p38 activation in KB human oral cancer cells

Kim,Jae-Sung; Oh,Dahye; Yim,Min-Ji; Park,Jin-Ju; Kang,Kyeong-Rok; Cho,In-A; Moon,Sung-Min; Oh,Ji-Su; You,Jae-Seek; Kim,Chun  Sung; Kim,Do  Kyung; Lee,Sook‑Young; Lee,Gyeong-Je; Im,Hee-Jeong; Kim,Su-Gwan

doi:10.3892/or.2015.3768

Berberine induces FasL-related apoptosis through p38 activation in KB human oral cancer cells

Authors:
- Jae-Sung Kim
- Dahye Oh
- Min-Ji Yim
- Jin-Ju Park
- Kyeong-Rok Kang
- In-A Cho
- Sung-Min Moon
- Ji-Su Oh
- Jae-Seek You
- Chun Sung Kim
- Do Kyung Kim
- Sook‑Young Lee
- Gyeong-Je Lee
- Hee-Jeong Im
- Su-Gwan Kim
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Affiliations: The Division of Natural Medical Science, College of Health Science, Chosun University, Dong-gu, Gwangju 501-759, Republic of Korea, Oral Biology Research Institute, School of Dentistry, Chosun University, Dong-gu, Gwangju 501-759, Republic of Korea, Regional Innovation Center for Dental Science and Engineering, Chosun University, Dong-gu, Gwangju 501-759, Republic of Korea, Department of Oral and Maxillofacial Surgery, School of Dentistry, Chosun University, Dong-gu, Gwangju 501-759, Republic of Korea, Department of Prosthodontics, School of Dentistry, Chosun University, Dong-gu, Gwangju 501-759, Republic of Korea, Department of Biochemistry, Rush University Medical Center, Chicago, IL 60612, USA
Published online on: January 29, 2015 https://doi.org/10.3892/or.2015.3768
Pages: 1775-1782

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Abstract

In the present study, we examined the anticancer properties of berberine in KB oral cancer cells with a specific focus on its cellular mechanism. Berberine did not affect the cell viability of the primary human normal oral keratinocytes that were used as a control. However, the viability of KB cells was found to decrease significantly in the presence of berberine in a dose-dependent manner. Furthermore, in KB cells, berberine induced the fragmentation of genomic DNA, changes in cell morphology, and nuclear condensation. In addition, caspase-3 and -7 activation, and an increase in apoptosis were observed. Berberine was also found to upregulate significantly the expression of the death receptor ligand, FasL. In turn, this upregulation triggered the activation of pro-apoptotic factors such as caspase-8, -9 and -3 and poly(ADP-ribose) polymerase (PARP). Furthermore, pro-apoptotic factors such as Bax, Bad and Apaf-1 were also significantly upregulated by berberine. Anti-apoptotic factors such as Bcl-2 and Bcl-xL were downregulated. Z-VAD-FMK, a cell-permeable pan-caspase inhibitor, suppressed the activation of caspase-3 and PARP. These results clearly indicate that berberine-induced cell death of KB oral cancer cells was mediated by both extrinsic death receptor-dependent and intrinsic mitochondrial-dependent apoptotic signaling pathways. In addition, berberine-induced upregulation of FasL was shown to be mediated by the p38 MAPK signaling pathway. We also found that berberine-induced migration suppression was mediated by downregulation of MMP-2 and MMP-9 through phosphorylation of p38 MAPK. In summary, berberine has the potential to be used as a chemotherapeutic agent, with limited side-effects, for the management of oral cancer.

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