Downregulation of secreted clusterin potentiates the lethality of sorafenib in hepatocellular carcinoma in association with the inhibition of ERK1/2 signals

Int J Mol Med. 2018 May;41(5):2893-2900. doi: 10.3892/ijmm.2018.3463. Epub 2018 Feb 6.

Abstract

Secretory clusterin (sCLU) is overexpressed in cancer and is associated with resistance to chemotherapy in several types of cancer, including hepatocellular carcinoma (HCC). Sorafenib (SOR), a multikinase inhibitor of Raf/mitogen‑activated protein kinase kinase/extracellular signal‑regulated kinase (ERK) signaling and the receptor tyrosine kinase, is recognized as the standard therapeutic strategy for patients with advanced HCC. However, the role of sCLU in the resistance of HCC to SOR remains to be fully elucidated. In the present study, sCLU was silenced by CLU short hairpin (sh)RNA in Bel‑7402 and SMMC‑7721 cell lines, following which the cells were treated with SOR. Cell proliferation was determined using a CCK‑8 assay. Apoptosis was quantified using flow cytometry. The production of sCLU, B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X sprotein and phosphorylated (p)ERK1/2 was analyzed using western blot analysis. The results showed that sCLU was overexpressed in three HCC cell lines. The downregulation of sCLU by CLU shRNA synergistically increased SOR sensitivity in the Bel‑7402 and SMMC‑7721 cells, and potentiated SOR‑induced cell apoptosis. In addition, silencing sCLU or combination with PD98059 decreased the SOR‑induced activation of pERK1/2. These findings indicate a novel treatment strategy for HCC.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Cell Line, Tumor
  • Clusterin / genetics*
  • Gene Silencing
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • MAP Kinase Signaling System / drug effects
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Phenylurea Compounds / pharmacology*
  • RNA, Small Interfering / genetics
  • Sorafenib

Substances

  • Antineoplastic Agents
  • CLU protein, human
  • Clusterin
  • Phenylurea Compounds
  • RNA, Small Interfering
  • Niacinamide
  • Sorafenib