Apoptosis signaling and BCL-2 pathways provide opportunities for novel targeted therapeutic strategies in hematologic malignances

Wu, Huanling; Medeiros, L. Jeffrey; Young, Ken H.

doi:10.1016/j.blre.2017.08.004

Cited by 68 publications

(45 citation statements)

References 244 publications

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“…Apoptosis is accompanied by changes in some cell morphologies, such as apoptotic bodies, nuclear condensation, and cell surface shrinkage. [24] DAPI staining was used to determine the nuclear morphology, which indicated that condensation of the nucleus Figure 3A). Caspase-3 is a critical factor in the terminal phase of apoptosis.…”

Section: Ppi Suppresses the C-kit And Akt Signaling Pathways In Kasummentioning

confidence: 99%

Polyphyllin I Inhibits Proliferation and Induces Apoptosis by Downregulating AML1‐ETO and Suppressing C‐KIT/Akt Signaling in t(8;21) Acute Myeloid Leukemia

Chai

et al. 2018

Chemistry & Biodiversity

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Polyphyllin I (PPI), a bioactive constituent extracted from traditional medicinal herbs, is cytotoxic to several cancer types. However, whether PPI can be used to treat t(8;21) acute myeloid leukemia (AML) cells requires further investigation. Here, we determined the inhibitory effects of PPI on t(8;21) AML cells by Cell Counting Kit-8 (CCK-8) and the trypan blue dye exclusion assay. DAPI staining and Wright-Giemsa staining were performed to check for apoptosis. Detection of apoptotic protein and AML1-ETO signaling protein expression were conducted by Western blot analysis. Our results suggested that PPI decreased growth and induced apoptosis in a dosage-dependent manner in the t(8;21) AML cell line Kasumi-1. PPI significantly downregulated AML1-ETO expression in a dosage- and time-dependent manner. PPI also upregulated P21 and downregulated survivin expression by reducing AML1-ETO. Mechanistically, PPI significantly reduced the expression of C-KIT, another therapeutic target for AML with t(8;21), followed by inhibition of Akt signaling. These results suggest that PPI can suppress growth and induce apoptosis of t(8;21) AML by suppressing the AML1-ETO and C-KIT/Akt signaling pathways. Therefore, PPI may be an anticancer therapeutic to treat t(8;21) AML.

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Section: Ppi Suppresses the C-kit And Akt Signaling Pathways In Kasummentioning

confidence: 99%

Polyphyllin I Inhibits Proliferation and Induces Apoptosis by Downregulating AML1‐ETO and Suppressing C‐KIT/Akt Signaling in t(8;21) Acute Myeloid Leukemia

Chai

et al. 2018

Chemistry & Biodiversity

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“…The Bcl‐2 family of apoptotic regulators is comprised of three subfamilies. The members of Mcl‐1, Bcl‐xL, and Bcl‐2 suppress apoptosis, whereas the Bax subfamily (eg, Bax and Bak) or the BH3 ‐only subfamily including Bad, Bid, Bok, Bik, Bim, and PUMA, promote apoptosis . The Bcl‐2 family members are critical to protect or induce mitochondrial dysfunction in a tightly regulated network.…”

Section: Introductionmentioning

confidence: 99%

“…The members of Mcl-1, Bcl-xL, and Bcl-2 suppress apoptosis, whereas the Bax subfamily (eg, Bax and Bak) or the BH3 -only subfamily including Bad, Bid, Bok, Bik, Bim, and PUMA, promote apoptosis. 7 The Bcl-2 family members are critical to protect or induce mitochondrial dysfunction in a tightly regulated network. PP2A as the Bcl-2 family of apoptosis regulators can directly dephosphorylate and activate the major proapoptotic molecule.…”

mentioning

confidence: 99%

Protein phosphatase 2A mediates JS‐K‐induced apoptosis by affecting Bcl‐2 family proteins in human hepatocellular carcinoma HepG2 cells

Liu

Huang

Chen

et al. 2018

J of Cellular Biochemistry

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Protein phosphatase 2A (PP2A) is an important enzyme within various signal transduction pathways. The present study was investigated PP2A mediates JS-K-induced apoptosis by affecting Bcl-2 family protein. JS-K showed diverse inhibitory effects in five HCC cell lines, especially HepG2 cells. JS-K caused a dose- and time-dependent reduction in cell viability and increased in levels of LDH release. Meanwhile, JS-K- induced apoptosis was characterized by mitochondrial membrane potential reduction, Hoechst 33342 /PI dual staining, release of cytochrome c (Cyt c), and activation of cleaved caspase-9/3. Moreover, JS-K-treatment could lead to the activation of protein phosphatase 2A-C (PP2A-C), decrease of anti-apoptotic Bcl-2 family-protein expression including p-Bcl-2 (Ser70), Bcl-2, Bcl-xL, and Mcl-1 as well as the increase of pro-apoptosis Bcl-2 family-protein including Bim, Bad, Bax, and Bak. Furthermore, JS-K caused a marked increase of intracellular NO levels while pre-treatment with Carboxy-PTIO (a NO scavenger) reduced the cytotoxicity effects and the apoptosis rate. Meanwhile, pre-treatment with Carboxy-PTIO attenuated the JS-K-induced up-regulation of PP2A, Cyt c, and cleaved-caspase-9/3 activation. The silencing PP2A-C by siRNA could abolish the activation of PP2A-C, down-regulation of anti-apoptotic Bcl-2 family-protein (p-Bcl-2, Bcl-2, Bcl-xL, and Mcl-1), increase of pro-apoptosis Bcl-2 family-protein (Bim, Bad, Bax, and Bak) and apoptotic-related protein (Cyt c, cleaved caspase-9/3) that were caused by JS-K in HepG2 cells. In addition, pre-treatment with OA (a PP2A inhibitor) also attenuated the above effects induced by JS-K. In summary, NO release from JS-K induces apoptosis through PP2A activation, which contributed to the regulation of Bcl-2 family proteins.

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“…A via extrínseca é ativada através de receptores de morte de superfície celular (Death receptor -DR) que se ligam em seus ligantes naturais, como TRAIL, FasL e TNF-α (Lordan et al, 2009). O TNFR (Receptores do Fator de Necrose Tumoral) contém uma superfamília de receptores (Hassan et al, 2014) como, receptor 1 do fator de necrose tumoral alfa (TNFR1), o ligante do receptor 1 do fator de necrose tumoral alfa (TRAIL-R1, DR4), o ligante do receptor 2 do fator de necrose tumoral alfa (TRAIL-R2, DR5), DR3, DR6 e Fas (CD95) (Mahalingam et al, 2009;Naoum et al 2017;Wu et al, 2018). Quando ocorre a ligação do ligante no DR, há formação do complexo de sinalização ligado a membrana (Lordan et al, 2009).…”

Section: Vias De Morte Celularunclassified

“…Sabe-se que alguns receptores da família TNF se ligam a proteínas adaptadoras TRADD (Receptor do fator de necrose tumoral tipo 1-associado a proteína do domínio de morte), juntamente com o FADD (Fas associado com a proteína do domínio de morte) formam o complexo DISC (complexo sinalizador indutor de morte) que é responsavel pelo recrutamento e ativação das caspases 8 e 10, desencadeando apoptose (Kufe et al, 2003;Wu et al, 2018). Ativação das caspases 8 e 10, podem ativar concomitantemente a via intrínseca da apoptose, através da clivagem da proteína Bid em tBid (Bid truncada) que é translocada para a mitocôndria (Lordan et al, 2009).…”

Section: Vias De Morte Celularunclassified

Características da toxicidade promovida por oxisteróis em células-tronco mesenquimais derivadas da medula óssea de pacientes com leucemia mieloide aguda

Paz¹

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Apoptosis signaling and BCL-2 pathways provide opportunities for novel targeted therapeutic strategies in hematologic malignances

Cited by 68 publications

References 244 publications

Polyphyllin I Inhibits Proliferation and Induces Apoptosis by Downregulating AML1‐ETO and Suppressing C‐KIT/Akt Signaling in t(8;21) Acute Myeloid Leukemia

Polyphyllin I Inhibits Proliferation and Induces Apoptosis by Downregulating AML1‐ETO and Suppressing C‐KIT/Akt Signaling in t(8;21) Acute Myeloid Leukemia

Protein phosphatase 2A mediates JS‐K‐induced apoptosis by affecting Bcl‐2 family proteins in human hepatocellular carcinoma HepG2 cells

Características da toxicidade promovida por oxisteróis em células-tronco mesenquimais derivadas da medula óssea de pacientes com leucemia mieloide aguda

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