Tumor Biology

, Volume 33, Issue 5, pp 1535–1541

ADAM10 overexpression confers resistance to doxorubicin-induced apoptosis in hepatocellular carcinoma

  • Cheng-lin Yang
  • Feng-qin Jiang
  • Feng Xu
  • Gui-xing Jiang
Research Article

DOI: 10.1007/s13277-012-0405-4

Cite this article as:
Yang, C., Jiang, F., Xu, F. et al. Tumor Biol. (2012) 33: 1535. doi:10.1007/s13277-012-0405-4

Abstract

Chemoresistance represents a major obstacle to successful treatment of hepatocellular carcinoma (HCC). A disintegrin and metalloproteinase 10 (ADAM10) is known to be frequently upregulated in many cancers. We aimed to determine the biological function of ADAM10 in the chemoresistance of HCC cells. Overexpression of ADAM10 in three HCC cell lines (HepG2, Hep3B, and Huh7) conferred protection against doxorubicin-induced apoptosis, as determined by Annexin V staining. Western blot analysis revealed that ADAM10-overexpressing cells had a significantly lower amount of cleaved caspase-3 and an elevated expression of myeloid cell leukemia-1 (Mcl-1), a prosurvival member of the Bcl-2 family. Conversely, RNA interference-mediated silencing of endogenous ADAM10 potentiated doxorubicin-induced apoptosis in HepG2 and Hep3B cells, which was coupled with increased cleavage of caspase-3 and decreased expression of Mcl-1. Ectopic expression of ADAM10 resulted in a marked increase in the phosphorylation of phosphatidylinositol 3-kinase (PI3-K) and Akt. Most interestingly, the pretreatment with the PI3-K inhibitor LY294002 significantly enhanced doxorubicin-induced apoptosis and diminished the Mcl-1 expression in ADAM10-overexpressing Huh7 cells. Our data provide evidence that ADAM10 plays an important role in modulating the chemosensitivity of HCC cells, which, at least partially, involves the activation of the PI3-K/Akt pathway. ADAM10 may be a promising target for the improvement of chemotherapeutic efficacy in HCC.

Keywords

Hepatocellular carcinoma (HCC)ADAM10ChemoresistanceApoptosisAkt

Supplementary material

13277_2012_405_MOESM1_ESM.doc (34 kb)
Supplementary Fig S1Hep3B cells were exposed to doxorubicin at concentrations of 0.1 to 5.0 μM for 24 h, and cell apoptosis was assessed by flow cytometry using the Annexin V-FITC Apoptosis Detection Kit. Doxorubicin at the concentration of 5.0 μM had a maximal induction of apoptosis. Error bars indicate standard deviations from 3 independent experiments. (DOC 34 kb)

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2012

Authors and Affiliations

  • Cheng-lin Yang
    • 1
    • 2
  • Feng-qin Jiang
    • 3
  • Feng Xu
    • 3
  • Gui-xing Jiang
    • 4
  1. 1.Ankang Central HospitalAnkangChina
  2. 2.Department of General SurgeryAffiliated Hospital of Ankang Vocational and Technical CollegeAnkangChina
  3. 3.Shaoxing People’s HospitalShaoxing Hospital of Zhejiang UniversityShaoxingChina
  4. 4.Department of Surgery, Second Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina