Epigallocatechin‑3‑gallate induces apoptosis in acute promyelocytic leukemia cells via a SHP‑1‑p38α MAPK‑Bax cascade

Abstract

Abstract. Acute promyelocytic leukemia (APL) is characterized by a specific chromosomal translation, resulting in a fusion gene that affects the differentiation, proliferation and apoptosis of APL cells. Epigallocatechin-3-gallate (EGCG), a catechin, exhibits numerous biological functions, including antitumor activities. Previous studies have reported that EGCG induces apoptosis in NB4 cells. However, the molecular mechanism underlying EGCG-induced apoptosis remains unclear. The present study aimed to determine the molecular basis of EGCG-induced apoptosis in NB4 cells. EGCG treatment significantly inhibited the viability of NB4 cells in a dose-dependent manner. In addition, EGCG treatment induced apoptosis and increased the levels of (Bcl-2-like protein 4) Bax protein expression. Moreover, EGCG treatment was able to increase phosphorylated (p)-p38α mitogen-activated protein kinase (MAPK) and Src homology 1 domain-containing protein tyrosine phosphatase (SHP-1) expression. Pretreatment with PD169316 (a p38 MAPK inhibitor) partially blocked EGCG-induced apoptosis and inhibited EGCG-mediated Bax expression. Similarly, pretreatment with NSC87877, an inhibitor of SHP-1, partially blocked EGCG-induced apoptosis and inhibited EGCG-mediated increases in p-p38α MAPK and Bax expression. Therefore, the results of the present study indicate that EGCG is able to induce apoptosis in NB4 cells via the SHP-1-p38αMAPK-Bax cascade. IntroductionAcute promyelocytic leukemia (APL), a unique subtype of acute myeloid leukemia, is characterized by a translocation between chromosomes 15 and 17 that encodes the oncogenic fusion protein promyelocytic leukemia/retinoic acid receptor-α (PML/RARα) (1). PML-RARα has an essential role in the development of APL by interfering with target genes that control differentiation, proliferation and apoptosis of APL cells (2). Considerable success in treating APL has been achieved using all-trans retinoic acid (3) and arsenic trioxide (4) in clinical settings. However, the toxicity of these molecules and the prevalence of drug-resistant forms of APL limit the clinical application of these drugs (5). Therefore, novel therapeutics to treat APL are urgently required.Src homology 1 domain-containing protein tyrosine phosphatase (SHP-1), also known as PTPN6 (6), consists of 17 exons and 16 introns and spans ~17 kb (7). SHP-1 controls the changes in the levels of intracellular phosphorylation, including JAK/STAT (8). SHP-1 exerts multiple biological functions through the alteration of several signaling pathways (9,10). A number of agonists and inhibitors of SHP-1 have been applied in clinical cancer therapies. For example, γ-tocotrienol (11) and regorafenib (12) have been used to treat breast tumors and colorectal cancer, respectively. Studies have reported that SHP-1 is highly expressed in normal hematopoietic cells (13) but weakly expressed in hematological malignancies, including Burkitt's lymphoma (14), APL (15) and chronic myeloid leukemia (16). Therefore, the present authors hypothesize that increases ...

Potential Therapeutic Targets of Epigallocatechin Gallate (EGCG), the Most Abundant Catechin in Green Tea, and Its Role in the Therapy of Various Types of Cancer

“…Moreover, another study demonstrated that epigallocatechin-3-gallate treatment meaningfully inhibited the viability of leukemia cells in a dose-dependent way. Besides, Epigallocatechin-3-gallate treatment induced apoptosis and increased the levels of Bax protein expression [ 111 ]. Study results reported that green tea compound targets PML/RARα oncoprotein in the degradation and potentiates differentiation of leukemia cells in combination with ATRA via PTEN [ 112 ].…”

(-)-Epigallocatechin-3-gallate induces interferon-λ2 expression to anti-influenza A virus in human bronchial epithelial cells (BEAS-2B) through p38 MAPK signaling pathway

“…These enzymes are serine-threonine protein kinases that regulate various cellular activities including proliferation, differentiation, apoptosis or survival, inflammation, and innate immunity (29). EGCG treatment was able to induce NB4 cell apoptosis by increasing phosphorylated (p)-p38α MAPK expression (30). In addition, other studies have found that EGCG also regulates ERK and JNK signaling pathways (31,32).…”

The beneficial and deleterious role of dietary polyphenols on chronic degenerative diseases by regulating gene expression

“…Kang et al indicated that polyphenols exerted anti-tumor actions as small molecular inhibitors of signaling cascades and src family kinase (38). EGCG induced apoptosis in human acute promyelocytic leukemia NB4 cells and increased the level of Bcl-2-associated X protein (Bax) protein expression via upregulating Src homology 1 domaincontaining protein tyrosine phosphatase (SHP-1)-p38αMAPK-Bax cascade (10). EGCG in combination with Am80 (a synthetic retinoid) synergistically induced apoptosis in human lung cancer cell line PC-9 and up-regulated expressions of growth arrest and DNA damage-inducible gene 153 (GADD153), death receptor 5, p21waf1 genes by increasing acetylation levels in nonhistone proteins such as p53, α-tubulin via down-regulation of histone deacetylase 4, 5, 6 (39).…”

“…2018; 12 (6): 526-536. cardioprotective actions and anti-platelet properties, etc. (9,10). However, the structure-activity relationship of dietary polyphenols is still unclear.…”