Pharmacological inhibition of Bcl-xL sensitizes osteosarcoma to doxorubicin
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Zuzanna Baranski1, Yvonne de Jong2, Trayana Ilkova1, Elisabeth F.P. Peterse2, Anne-Marie Cleton-Jansen2, Bob van de Water1, Pancras C.W. Hogendoorn2, Judith V.M.G. Bovée2, Erik H.J. Danen1
1Division of Toxicology, Leiden/Academic Center for Drug Research, Leiden University, 2300 RA Leiden, The Netherlands
2Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
Erik H.J. Danen, e-mail: firstname.lastname@example.org
Keywords: osteosarcoma, apoptosis, autophagy, Bcl-xL, doxorubicin
Received: May 21, 2015 Accepted: September 14, 2015 Published: September 25, 2015
High-grade conventional osteosarcoma is the most common primary bone tumor. Prognosis for osteosarcoma patients is poor and resistance to chemotherapy is common. We performed an siRNA screen targeting members of the Bcl-2 family in human osteosarcoma cell lines to identify critical regulators of osteosarcoma cell survival. Silencing the anti-apoptotic family member Bcl-xL but also the pro-apoptotic member Bak using a SMARTpool of siRNAs as well as 4/4 individual siRNAs caused loss of viability. Loss of Bak impaired cell cycle progression and triggered autophagy. Instead, silencing Bcl-xL induced apoptotic cell death. Bcl-xL was expressed in clinical osteosarcoma samples but mRNA or protein levels did not significantly correlate with therapy response or survival. Nevertheless, pharmacological inhibition of a range of Bcl-2 family members showed that inhibitors targeting Bcl-xL synergistically enhanced the response to the chemotherapeutic agent, doxorubicin. Indeed, in osteosarcoma cells strongly expressing Bcl-xL, the Bcl-xL-selective BH3 mimetic, WEHI-539 potently enhanced apoptosis in the presence of low doses of doxorubicin. Our results identify Bcl-xL as a candidate drug target for sensitization to chemotherapy in patients with osteosarcoma.
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