Sensitization of multidrug resistant human ostesarcoma cells to Apo2 Ligand/TRAIL-induced apoptosis by inhibition of the Akt/PKB kinase

  • Authors:
    • Vittoria Cenni
    • Nadir M. Maraldi
    • Alessandra Ruggeri
    • Paola Secchiero
    • Rosalba Del Coco
    • Anto De Pol
    • Lucio Cocco
    • Sandra Marmiroli
  • View Affiliations

  • Published online on: December 1, 2004     https://doi.org/10.3892/ijo.25.6.1599
  • Pages: 1599-1608
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Abstract

Chemotherapeutic agents have been used for the treatment of patients with osteosarcoma (OS). However, inherent or acquired resistance to these agents is a serious problem in the management of OS patients. The emergence of the multidrug resistance (MDR) phenotype in cancer cells is often associated with the overexpression of P-glycoprotein, encoded by the multidrug resistance gene MDR-1. The administration of some of the most common chemotherapeutic agents to these cells becomes ineffective because of their P-gp-driven efflux from the cell. Apo2L/TRAIL is a member of the tumor necrosis factor (TNF) family of cytokines that is considered to induce death of cancer cells but not normal cells. Its powerful apoptotic activity is mediated through its cell surface death domain-containing receptors, TRAIL-R1/DR4 and TRAIL-R2/DR5, which in turn spread the signal in the cytosol through the activation of the caspase cascade. The Akt/PKB kinase is an important cell survival protein which is regulated by D3-phosphoinositides. High Akt expression and activity levels are well documented in many types of tumors, which very often show an altered PI3-K/Akt/PTEN pathway. In this study the U2OS human osteosarcoma cell line and its multidrug resistant (MDR) subline that overexpresses MDR-1 gene, MDR-U2OS, have been analyzed for their responsiveness to TRAIL. In conflict with the presence of active DR4 and DR5 receptors in both clones, U2OS cells exhibited only a low responsiveness to TRAIL, while the MDR-U2OS subline did exhibit a marked TRAIL sensitivity. An analysis of the post-receptor events showed that TRAIL responsiveness correlates with a reduced expression of endogenous Akt. In fact, expression in MDR-U2OS cells of a constitutively active Akt strongly decreased their sensitivity to TRAIL. The identification of Akt as a key modulator of TRAIL responsiveness could help to design TRAIL-based combinations for treatment of osteosarcoma. Moreover, the discovery that multidrug resistant osteosarcomas are highly sensitive to TRAIL-induced apoptosis indicates TRAIL as a new candidate for the treatment of multidrug resistant bone malignancies.

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December 2004
Volume 25 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Cenni V, Maraldi NM, Ruggeri A, Secchiero P, Del Coco R, De Pol A, Cocco L and Marmiroli S: Sensitization of multidrug resistant human ostesarcoma cells to Apo2 Ligand/TRAIL-induced apoptosis by inhibition of the Akt/PKB kinase. Int J Oncol 25: 1599-1608, 2004
APA
Cenni, V., Maraldi, N.M., Ruggeri, A., Secchiero, P., Del Coco, R., De Pol, A. ... Marmiroli, S. (2004). Sensitization of multidrug resistant human ostesarcoma cells to Apo2 Ligand/TRAIL-induced apoptosis by inhibition of the Akt/PKB kinase. International Journal of Oncology, 25, 1599-1608. https://doi.org/10.3892/ijo.25.6.1599
MLA
Cenni, V., Maraldi, N. M., Ruggeri, A., Secchiero, P., Del Coco, R., De Pol, A., Cocco, L., Marmiroli, S."Sensitization of multidrug resistant human ostesarcoma cells to Apo2 Ligand/TRAIL-induced apoptosis by inhibition of the Akt/PKB kinase". International Journal of Oncology 25.6 (2004): 1599-1608.
Chicago
Cenni, V., Maraldi, N. M., Ruggeri, A., Secchiero, P., Del Coco, R., De Pol, A., Cocco, L., Marmiroli, S."Sensitization of multidrug resistant human ostesarcoma cells to Apo2 Ligand/TRAIL-induced apoptosis by inhibition of the Akt/PKB kinase". International Journal of Oncology 25, no. 6 (2004): 1599-1608. https://doi.org/10.3892/ijo.25.6.1599