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Enhanced G1 arrest and apoptosis via MDM4/MDM2 double knockdown and MEK inhibition in wild‑type TP53 colon and gastric cancer cells with aberrant KRAS signaling

  • Authors:
    • Xiaoxuan Wang
    • Yoshiyuki Yamamoto
    • Mamiko Imanishi
    • Xiaochen Zhang
    • Masashi Sato
    • Akinori Sugaya
    • Mitsuaki Hirose
    • Shinji Endo
    • Yukikazu Natori
    • Toshikazu Moriwaki
    • Kenji Yamato
    • Ichinosuke Hyodo
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305‑8575, Japan, Division of Gastroenterology, Ibaraki Prefectural Central Hospital, Kasama, Ibaraki 309‑1793, Japan, BioThinkTank Co. Ltd., Yokohama, Kanagawa 220‑0012, Japan
    Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 558
    |
    Published online on: May 25, 2021
       https://doi.org/10.3892/ol.2021.12819
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Abstract

Murine double minute homolog 2 (MDM2) is an oncoprotein that induces p53 degradation via ubiquitin‑ligase activity. MDM4 cooperates with MDM2‑mediated p53 degradation, directly inhibiting p53 transcription by binding to its transactivation domain. Our previous study reported that the simultaneous inhibition of MDM2 and MDM4 using nutlin‑3 (an inhibitor of the MDM2‑p53 interaction) and chimeric small interfering RNA with DNA‑substituted seed arms (named chiMDM2 and chiMDM4) more potently activated p53 than the MDM2 or MDM4 inhibitor alone and synergistically augmented antitumor effects in various types of cancer cells with the wild‑type (wt) TP53. Recently, the synergism of MDM2 and mitogen‑activated protein kinase kinase (MEK) inhibitors has been demonstrated in wt TP53 colorectal and non‑small cell lung cancer cells harboring mutant‑type (mt) KRAS. The current study examined whether chiMDM4 augmented the synergistic antitumor effects of MDM2 and MEK inhibition using chiMDM2 or nutlin‑3 and trametinib, respectively. ChiMDM2 and trametinib used in combination demonstrated a synergistic antitumor activity in HCT116 and LoVo colon cancer cells, and SNU‑1 gastric cancer cells harboring wt TP53 and mt KRAS. Furthermore, chiMDM4 synergistically enhanced this combinational effect. Similar results were observed when nutlin‑3 was used instead of chiMDM2. MDM4/MDM2 double knockdown combined with trametinib treatment enhanced G1 arrest and apoptosis induction. This was associated with the accumulation of p53, suppression of phosphorylated‑extracellular signal‑regulated kinase 2, inhibition of retinoblastoma phosphorylation, suppression of E2F1‑activated proteins, and potent activation of pro‑apoptotic proteins, such as Fas and p53 upregulated modulator of apoptosis. The results inidcated that the triple inhibition of MDM4, MDM2 and MEK exerted a potent antitumor effect in wt TP53 colon and gastric cancer cells with mt KRAS. Simultaneous activation of p53 and inhibition of aberrant KRAS signaling may be a rational treatment strategy for gastrointestinal tumors.
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Copy and paste a formatted citation
Spandidos Publications style
Wang X, Yamamoto Y, Imanishi M, Zhang X, Sato M, Sugaya A, Hirose M, Endo S, Natori Y, Moriwaki T, Moriwaki T, et al: Enhanced G1 arrest and apoptosis via MDM4/MDM2 double knockdown and MEK inhibition in wild‑type <em>TP53</em> colon and gastric cancer cells with aberrant KRAS signaling. Oncol Lett 22: 558, 2021.
APA
Wang, X., Yamamoto, Y., Imanishi, M., Zhang, X., Sato, M., Sugaya, A. ... Hyodo, I. (2021). Enhanced G1 arrest and apoptosis via MDM4/MDM2 double knockdown and MEK inhibition in wild‑type <em>TP53</em> colon and gastric cancer cells with aberrant KRAS signaling. Oncology Letters, 22, 558. https://doi.org/10.3892/ol.2021.12819
MLA
Wang, X., Yamamoto, Y., Imanishi, M., Zhang, X., Sato, M., Sugaya, A., Hirose, M., Endo, S., Natori, Y., Moriwaki, T., Yamato, K., Hyodo, I."Enhanced G1 arrest and apoptosis via MDM4/MDM2 double knockdown and MEK inhibition in wild‑type <em>TP53</em> colon and gastric cancer cells with aberrant KRAS signaling". Oncology Letters 22.1 (2021): 558.
Chicago
Wang, X., Yamamoto, Y., Imanishi, M., Zhang, X., Sato, M., Sugaya, A., Hirose, M., Endo, S., Natori, Y., Moriwaki, T., Yamato, K., Hyodo, I."Enhanced G1 arrest and apoptosis via MDM4/MDM2 double knockdown and MEK inhibition in wild‑type <em>TP53</em> colon and gastric cancer cells with aberrant KRAS signaling". Oncology Letters 22, no. 1 (2021): 558. https://doi.org/10.3892/ol.2021.12819
Copy and paste a formatted citation
x
Spandidos Publications style
Wang X, Yamamoto Y, Imanishi M, Zhang X, Sato M, Sugaya A, Hirose M, Endo S, Natori Y, Moriwaki T, Moriwaki T, et al: Enhanced G1 arrest and apoptosis via MDM4/MDM2 double knockdown and MEK inhibition in wild‑type <em>TP53</em> colon and gastric cancer cells with aberrant KRAS signaling. Oncol Lett 22: 558, 2021.
APA
Wang, X., Yamamoto, Y., Imanishi, M., Zhang, X., Sato, M., Sugaya, A. ... Hyodo, I. (2021). Enhanced G1 arrest and apoptosis via MDM4/MDM2 double knockdown and MEK inhibition in wild‑type <em>TP53</em> colon and gastric cancer cells with aberrant KRAS signaling. Oncology Letters, 22, 558. https://doi.org/10.3892/ol.2021.12819
MLA
Wang, X., Yamamoto, Y., Imanishi, M., Zhang, X., Sato, M., Sugaya, A., Hirose, M., Endo, S., Natori, Y., Moriwaki, T., Yamato, K., Hyodo, I."Enhanced G1 arrest and apoptosis via MDM4/MDM2 double knockdown and MEK inhibition in wild‑type <em>TP53</em> colon and gastric cancer cells with aberrant KRAS signaling". Oncology Letters 22.1 (2021): 558.
Chicago
Wang, X., Yamamoto, Y., Imanishi, M., Zhang, X., Sato, M., Sugaya, A., Hirose, M., Endo, S., Natori, Y., Moriwaki, T., Yamato, K., Hyodo, I."Enhanced G1 arrest and apoptosis via MDM4/MDM2 double knockdown and MEK inhibition in wild‑type <em>TP53</em> colon and gastric cancer cells with aberrant KRAS signaling". Oncology Letters 22, no. 1 (2021): 558. https://doi.org/10.3892/ol.2021.12819
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