Research Article

Tumor Biology

, Volume 33, Issue 5, pp 1535-1541

First online:

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

  • Cheng-lin YangAffiliated withAnkang Central HospitalDepartment of General Surgery, Affiliated Hospital of Ankang Vocational and Technical College
  • , Feng-qin JiangAffiliated withShaoxing People’s Hospital, Shaoxing Hospital of Zhejiang University
  • , Feng XuAffiliated withShaoxing People’s Hospital, Shaoxing Hospital of Zhejiang University
  • , Gui-xing JiangAffiliated withDepartment of Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University Email author 

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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.


Hepatocellular carcinoma (HCC) ADAM10 Chemoresistance Apoptosis Akt