Abstract
Luteolin, a flavonoid nutraceutical abundant in vegetables and fruits, exhibits a wide range of bioactive properties, including antioxidant, anti-inflammatory and anti-cancer activities. Pituitary tumor-transforming gene 1 (PTTG1), an oncoprotein that regulates cell proliferation, is highly expressed in several types of cancer cells including leukemia. In this study, we aim to investigate the anti-cancer effects of luteolin on cells with differential PTTG1 expression and their underlying mechanisms in human myeloid leukemia cells. Methyl thiazolyl tetrazolium (MTT) assay data showed that luteolin (25–100 μM) significantly reduced cell viability in THP-1, HL-60 and K562 cells but did not affect normal peripheral blood mononuclear cells (PBMCs). Flow cytometric analysis and Western blot data demonstrated that luteolin induced a stronger apoptosis on undifferentiated myeloid leukemia cells with higher PTTG1 protein levels than on 12-myristate 13-acetate (PMA)- or all-trans-retinoic acid (ATRA)-differentiated cells with lower PTTG1 expression. Furthermore, PTTG1 knockdown by shRNA in leukemia cells suppressed cell proliferation, arrested cell-cycle progression and impaired the effectiveness of luteolin on cell-cycle regulation. Moreover, PTTG1-knockdown cells with luteolin exposure presented a reduction of the apoptotic proteins and maintained higher levels of the anti-apoptotic proteins such as Mcl-1, Bcl-2 and p21, which exhibited greater resistance to apoptosis. Finally, microarray analysis showed that 20 genes associated with cell proliferation, such as CXCL10, VEGFA, TNF, TP63 and FGFR1, were dramatically down-regulated in PTTG1-knockdown cells. Our current findings clearly demonstrate that luteolin-triggered leukemic cell apoptosis is modulated by the differential expression of the PTTG1. PTTG1 oncoprotein overexpression may modulate cell proliferation-related regulators and enhance the response of myeloid leukemia cells to luteolin. Luteolin is beneficial for the treatment of cancer cells with highly expressed PTTG1 oncoprotein.
Highlights
Human myeloid leukemia is a highly heterogeneous neoplasm characterized by genetic mutations that enhance the proliferation of myeloid blasts, promote their self-renewal, and/or block hematopoietic differentiation
Similar effects were found in human myeloid leukemia HL-60 and K562 cell lines treated with luteolin
We previously demonstrated that Pituitary tumor-transforming gene 1 (PTTG1) is not expressed in normal peripheral blood mononuclear cells (PBMCs) and that PTTG1 expression is significantly reduced in phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cell lines [23]
Summary
Human myeloid leukemia is a highly heterogeneous neoplasm characterized by genetic mutations that enhance the proliferation of myeloid blasts, promote their self-renewal, and/or block hematopoietic differentiation. The current treatment of patients with leukemia still yields poor outcomes, with expected cure rates in the order of 30–40%, depending on the biological characteristics of the leukemic clone. Drug resistance and severe side effects of chemotherapeutic agents reduce the clinical efficacy of leukemia therapy [3,4]. There is an urgent need to develop alternative regimens or synergistic drugs with low toxicity and high specificity for the improved efficacy of current leukemia therapy. Dietary phytochemicals are found to be an important resource to develop effective anti-cancer agents [5]. Many studies have found that these natural agents successfully interrupt DNA replication, arrest cell-cycle progression, and trigger apoptosis of leukemia cells but do not affect normal or quiescent blood cells [6,7,8,9]
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