Research Article: Targeting of X-linked inhibitor of apoptosis protein and PI3-kinase/AKT signaling by embelin suppresses growth of leukemic cells

Date Published: July 13, 2017

Publisher: Public Library of Science

Author(s): Kirti S. Prabhu, Kodappully S. Siveen, Shilpa Kuttikrishnan, Ahmad Iskandarani, Magdalini Tsakou, Iman W. Achkar, Lubna Therachiyil, Roopesh Krishnankutty, Aijaz Parray, Michal Kulinski, Maysaloun Merhi, Said Dermime, Ramzi M. Mohammad, Shahab Uddin, Eric Asselin.

http://doi.org/10.1371/journal.pone.0180895

Abstract

The X-linked inhibitor of apoptosis (XIAP) is a viable molecular target for anticancer drugs that overcome apoptosis-resistance of malignant cells. XIAP is an inhibitor of apoptosis, mediating through its association with BIR3 domain of caspase 9. Embelin, a quinone derivative isolated from the Embelia ribes plant, has been shown to exhibit chemopreventive, anti-inflammatory, and apoptotic activities via inhibiting XIAP activity. In this study, we found that embelin causes a dose-dependent suppression of proliferation in leukemic cell lines K562 and U937. Embelin mediated inhibition of proliferation correlates with induction of apoptosis. Furthermore, embelin treatment causes loss of mitochondrial membrane potential and release of cytochrome c, resulting in subsequent activation of caspase-3 followed by polyadenosin-5’-diphosphate-ribose polymerase (PARP) cleavage. In addition, embelin treatment of leukemic cells results in a decrease of constitutive phosphorylations/activation level of AKT and downregulation of XIAP. Gene silencing of XIAP and AKT expression showed a link between XIAP expression and activated AKT in leukemic cells. Interestingly, targeting of XIAP and PI3-kinase/AKT signaling augmented inhibition of proliferation and induction of apoptosis in leukemic cells. Altogether these findings raise the possibility that embelin alone or in combination with inhibitors of PI3-kinase/AKT pathway may have therapeutic usage in leukemia and possibly other malignancies with up-regulated XIAP pathway.

Partial Text

Resistance to apoptosis is one of the hallmarks that promotes cancer development and progression in various cancers including leukemia [1, 2]. Furthermore, escape from apoptosis is the important causes of failure of antileukemic effects of many conventional therapeutic drugs as many of anticancer drugs exhibit anticancer activity via inducing apoptosis in malignant cells [3]. X-linked inhibitor of apoptosis protein (XIAP) is a prominent protein member of the inhibitor of apoptosis (IAP) that collectively involved inhibition of apoptosis and thereby improving the survival of cancer cell [4–6]. XIAP is the only member of the IAPs that has been shown to inhibit the functionality of both; the initiation caspase (caspase-9) as well as executioner caspase (caspase-3) thereby limiting the role of apoptosis in cancer cells [7, 8]. There is accumulating evidence that XIAP is involved in regulating apoptosis sensitivity of malignant cells and also exhibits prognostic implications [9, 10] as high expression of XIAP has been reported in leukemic blasts and correlates with poor survival [11]. XIAP protein and mRNA levels have been associated with chemoresistance and poor clinical outcome in leukemic patients [11–13]. Overexpression of XIAP has been shown to be associated with activated AKT in many cancers including leukemia [14, 15]. Activation of AKT is involved in the protection of XIAP degradation by chemotherapeutic agents in malignant cells [16]. Recently we and other have shown a functional association of AKT and XIAP in cancer cells [4, 17, 18].

Comparisons between groups were made using the paired Student’s t-test. Values of P<0.05 were considered statistically significant. Statistical signifiacne is shown with * (P<0.001), # (P<0.01) and $ (P<0.05). Data are expressed as the mean ± S.D. Deregulation of programmed cell death, i.e., apoptosis, and related signaling pathways are involved in growth and proliferation of malignant cells and are critical processes in sustaining the unlimited progression and survival in cancer cells. These pathways are viable targets for designing effective drugs for the management and prevention of cancer. Many studies have demonstrated that XIAP is a potential therapeutic target for cancer cells as overexpression of XIAP is found in many cancers [42–44] and has been linked to the resistance to many therapeutic agents [45]. Interestingly, gene silencing using siRNA technology restores chemo-sensitivity of drugs to various cancer cell lines [46, 47]. In summary, embelin-induces inhibition of cell proliferation of leukemic cells via inducing intrinsic apoptotic pathway. Furthermore, targeting XIAP and AKT simultaneously induced efficient apoptotic cell death in leukemic cells. These findings suggest that XIAP expression is an important molecular target for therapeutic intervention of such malignancies.   Source: http://doi.org/10.1371/journal.pone.0180895

 

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