Open Access

Connexin-dependent gap junction enhancement is involved in the synergistic effect of sorafenib and all-trans retinoic acid on HCC growth inhibition

  • Authors:
    • Yan Yang
    • Shu-Kui Qin
    • Qiong Wu
    • Zi-Shu Wang
    • Rong-Sheng Zheng
    • Xu-Hui Tong
    • Hao Liu
    • Liang Tao
    • Xian-Di He
  • View Affiliations

  • Published online on: December 5, 2013     https://doi.org/10.3892/or.2013.2894
  • Pages: 540-550
  • Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Increasing gap junction activity in tumor cells provides a target by which to enhance antineoplastic therapies. Previously, several naturally occurring agents, including all-trans retinoic acid (ATRA) have been demonstrated to increase gap junctional intercellular communication (GJIC) in a number of types of cancer cells. In the present study, we investigated in vitro whether ATRA modulates the response of human hepatocellular carcinoma (HCC) cells to sorafenib, the only proven oral drug for advanced HCC, and the underlying mechanisms. HepG2 and SMMC-7721 cells were treated with sorafenib and/or ATRA, and cell proliferation and apoptosis were analyzed; the role of GJIC was also explored. We found that ATRA, at non-toxic concentrations, enhanced sorafenib-induced growth inhibition in both HCC cell lines, and this effect was abolished by two GJIC inhibitors, 18-α-GA and oleamide. Whereas lower concentrations of sorafenib (5 µM) or ATRA (0.1 or 10 µM) alone modestly induced GJIC activity, the combination of sorafenib plus ATRA resulted in a strong enhancement of GJIC. However, the action paradigm differed in the HepG2 and SMMC-7721 cells, with the dominant effect of GJIC dependent on the cell-specific connexin increase in protein amounts and relocalization. RT-PCR assay further revealed a transcriptional modification of the key structural connexin in the two cell lines. Thus, a connexin-dependent gap junction enhancement may play a central role in ATRA plus sorafenib synergy in inhibiting HCC cell growth. Since both agents are available for human use, the combination treatment represents a future profitable strategy for the treatment of advanced HCC.
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2014-February
Volume 31 Issue 2

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Yang Y, Qin S, Wu Q, Wang Z, Zheng R, Tong X, Liu H, Tao L and He X: Connexin-dependent gap junction enhancement is involved in the synergistic effect of sorafenib and all-trans retinoic acid on HCC growth inhibition. Oncol Rep 31: 540-550, 2014.
APA
Yang, Y., Qin, S., Wu, Q., Wang, Z., Zheng, R., Tong, X. ... He, X. (2014). Connexin-dependent gap junction enhancement is involved in the synergistic effect of sorafenib and all-trans retinoic acid on HCC growth inhibition. Oncology Reports, 31, 540-550. https://doi.org/10.3892/or.2013.2894
MLA
Yang, Y., Qin, S., Wu, Q., Wang, Z., Zheng, R., Tong, X., Liu, H., Tao, L., He, X."Connexin-dependent gap junction enhancement is involved in the synergistic effect of sorafenib and all-trans retinoic acid on HCC growth inhibition". Oncology Reports 31.2 (2014): 540-550.
Chicago
Yang, Y., Qin, S., Wu, Q., Wang, Z., Zheng, R., Tong, X., Liu, H., Tao, L., He, X."Connexin-dependent gap junction enhancement is involved in the synergistic effect of sorafenib and all-trans retinoic acid on HCC growth inhibition". Oncology Reports 31, no. 2 (2014): 540-550. https://doi.org/10.3892/or.2013.2894