Celecoxib inhibits proliferation and survival of chronic myelogeous leukemia (CML) cells via AMPK-dependent regulation of β-catenin and mTORC1/2.

Beatrice Riva,Alberto Minassi,Paolo Salomoni,Armando A Genazzani,Samanta A Mariani,Pier Luigi Canonico,Valentina Minieri,Marco De Dominici,Fabrizio Condorelli,Bruno Calabretta,Ilaria Gnemmi

doi:10.18632/oncotarget.13146

Abstract

CML is effectively treated with tyrosine kinase inhibitors (TKIs). However, the efficacy of these drugs is confined to the chronic phase of the disease and development of resistance to TKIs remains a pressing issue. The anti-inflammatory COX2 inhibitor celecoxib has been utilized as anti-tumour drug due to its anti-proliferative activity. However, its effects in hematological malignancies, in particular CML, have not been investigated yet. Thus, we tested biological effects and mechanisms of action of celecoxib in Philadelphia-positive (Ph+) CML and ALL cells.We show here that celecoxib suppresses the growth of Ph+ cell lines by increasing G1-phase and apoptotic cells and reducing S- and G2-phase cells. These effects were independent of COX2 inhibition but required the rapid activation of AMP-activated protein kinase (AMPK) and the consequent inhibition mTORC1 and 2. Treatment with celecoxib also restored GSK3β function and led to down-regulation of β-catenin activity through transcriptional and post-translational mechanisms, two effects likely to contribute to Ph+ cell growth suppression by celecoxib.Celecoxib inhibited colony formation of TKI-resistant Ph+ cell lines including those with the T315I BCR-ABL mutation and acted synergistically with imatinib in suppressing colony formation of TKI-sensitive Ph+ cell lines. Finally, it suppressed colony formation of CD34+ cells from CML patients, while sparing most CD34+ progenitors from healthy donors, and induced apoptosis of primary Ph+ ALL cells.Together, these findings indicate that celecoxib may serve as a COX2-independent lead compound to simultaneously target the mTOR and β-catenin pathways, key players in the resistance of CML stem cells to TKIs.

Highlights

Celecoxib is a sulfonamide COX2 inhibitor (COXib) used in the therapy of osteoarthritis and rheumatoid arthritis
Chronic myelogenous leukemia (CML), a myeloproliferative disorder caused by the BCR-ABL1 oncoprotein, is an ideal model to dissect COX2-dependent and COX2-independent mechanisms of celecoxib growth inhibition because the role of many signal transduction pathways in CML cell proliferation and survival is well established, allowing the effects of celecoxib to be linked to the modulation of specific BCR-ABL-regulated pathways
Immunoblots of cell lysates revealed that the three cell lines express very low levels of COX1, which is not targeted by celecoxib, whereas expression of COX2 was not detectable (Figure 1B)

Summary

Introduction

Celecoxib is a sulfonamide COX2 inhibitor (COXib) used in the therapy of osteoarthritis and rheumatoid arthritis. In addition to its anti-inflammatory activity, celecoxib exerts anti-proliferative effects on transformed cells, as shown in some solid tumors. It is the only COXib used for the therapy of Familial Adenomatous Polyposis (FAP) patients with the goal to prevent its evolution toward colon cancer [1,2,3] by inhibiting the COX2-dependent secretion of prostaglandin E2 by adenomatous cells. Several reports indicate that celecoxib exerts cell-autonomous anti-proliferative and proapoptotic effects in cancer cell lines that do not express COX2 [4,5] In line with these findings, dimethylcelecoxib, a close structural analogue of celecoxib that lacks anti-COX2 activity (“non-COXib”), mimics the antitumor effects of celecoxib [6,7,8]. Drugs not previously known to play a role in CML, such as the anti-diabetic drug pioglitazone, appear to have important and unexpected effects in CML [13], raising the possibility that growth-inhibitory effects of celecoxib in Ph+ cells may be therapeutically relevant

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