Arsenic trioxide induces apoptosis and G2/M phase arrest by inducing Cbl to inhibit PI3K/Akt signaling and thereby regulate p53 activation

Li, Yingchun; Qu, Xiujuan; Qu, Junle; Zhang, Ye; Liu, Jing; Teng, Yuee; Hu, Xuejun; Hou, Kezuo; Liu, Yunpeng

doi:10.1016/j.canlet.2009.04.035

Cited by 75 publications

(56 citation statements)

References 30 publications

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“…The present results demonstrate that ATO up-regulates Cbl-b expression in the process of apoptosis in both HL60 and RBL-2H3 cells. These events imply the importance of Cbl-b up-regulation by ATO, which is consistent with our previous assumption regarding NB4 cells (26). The NB4 cell line is characterized by the PML/ RARα fusion protein and ATO strongly promotes apoptosis in NB4 cells by modulating and degrading the fusion protein (6).…”

Section: Discussionsupporting

confidence: 90%

“…In addition, DN Cbl-b overexpression significantly induced G2/M phase arrest in the process of apoptosis by ATO. Higher Akt activation might influence the vital substrates, such as p53, which is the determinant in the action of ATO, apoptosis or G2/M phase arrest (26). Consistent with this explanation, the PI3K/Akt inhibitor LY294002 significantly enhanced ATO-induced apoptosis in both cells, and also markedly reversed ATO-induced G2/M phase arrest in DN Cbl-b overexpressing cells.…”

Section: Discussionmentioning

confidence: 64%

“…The effect of ATO on HL60 cell viability was measured by the Trypan blue exclusion assay (26). At assay time, HL60 cells were collected, mixed with an equal volume of PBS containing 0.4% Trypan blue dye, and manually counted.…”

Section: Cell Viability Assaymentioning

confidence: 99%

“…Western blotting was performed using standard techniques (26). Briefly, cells were washed twice with PBS and lysed in 1% Triton lysis buffer (1% Triton X-100, 50 mM Tris-Cl, pH 7.4, 150 mM NaCl, 10 mM EDTA, 100 mM NaF, 1 mM Na 3 VO 4 , 1 mM PMSF, and 2 μg/mL aprotinin) on ice.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…One of our recent www.bjournal.com.br Braz J Med Biol Res 44(2) 2011 investigations showed that Cbl-b sensitizes both leukemia and gastric cancer cells to anthracyclines by modulating the ERK and Akt survival pathways (25). Another investigation also demonstrated that inhibition of PI3K/Akt signaling by Cbl (Cbl-b and c-Cbl) may be involved in both ATO-induced apoptosis of NB4 cells and ATO-induced G2/M phase arrest of gastric cancer cells (26). Since this result was derived from indirect evidence with pharmacologic inhibitors of PI3K/ Akt and proteasome, it is still unclear whether or not Cbl-b is involved in the action of ATO on AML cells.…”

Section: Introductionmentioning

confidence: 99%

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E3 ubiquitin ligase Cbl-b potentiates the apoptotic action of arsenic trioxide by inhibiting the PI3K/Akt pathway

Li¹,

Qu²,

Qu³

et al. 2011

Braz J Med Biol Res

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Arsenic trioxide (ATO) is a strong inducer of apoptosis in malignant hematological cells. Inducible phosphatidyl inositol 3 kinase (PI3K)-Akt activation promotes resistance to ATO. In the present study, we evaluated whether E3 ubiquitin ligase Cbl-b, a negative regulator of PI3K activation, is involved in the action of ATO. The effect of ATO on cell viability was measured by the Trypan blue exclusion assay or by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was determined by flow cytometry and protein expression was assayed by Western blotting. ATO decreased the viability of HL60 cells and induced cellular apoptosis, which was accompanied by transient activation of Akt. The PI3K/Akt inhibitor, LY294002, significantly increased ATO-induced apoptosis (P < 0.05). In addition, ATO up-regulated the expression of Cbl-b proteins. Furthermore, ATO inhibited cell viability with an IC 50 of 18.54 μM at 24 h in rat basophilic leukemia-2H3 cells. ATO induced cellular apoptosis with transient activation of Akt and Cbl-b was also up-regulated. Rat basophilic leukemia-2H3 cells transfected with a dominant negative (DN) Cbl-b mutation showed overexpression of Cbl-b (DN) and enhanced Akt activation. Compared with cells transfected with vector, ATO-induced apoptosis was decreased and G2/M phase cells were increased at the same concentration (P < 0.05). The PI3K/Akt inhibitor, LY294002, re-sensitized Cbl-b (DN) overexpressing cells to ATO and reversed G2/M arrest (P < 0.05). Taken together, these results suggest that Cbl-b potentiates the apoptotic action of ATO by inhibition of the PI3K/Akt pathway.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 64%

Section: Cell Viability Assaymentioning

confidence: 99%

Section: Western Blot Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

E3 ubiquitin ligase Cbl-b potentiates the apoptotic action of arsenic trioxide by inhibiting the PI3K/Akt pathway

Li¹,

Qu²,

Qu³

et al. 2011

Braz J Med Biol Res

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Role in Chemotherapy

Mann

Lemaire

2015

Arsenic

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Mechanistic effects of arsenic trioxide on acute promyelocytic leukemia and other types of leukemias

Yousefnia

2021

Cell Biology International

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Acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia characterized with a translocation between promyelocytic leukemia gene (PML) on chromosome 15 and retinoic acid receptor alpha gene (RARα) on chromosome 17. Transcription of this fusion gene results in PML/RARα fusion protein blocking expression of critical genes involved in differentiation of myeloid cells through interaction with RAR element. PML/RARα fusion protein prevents normal function of PML and RARα as well as inhibiting apoptosis. Arsenic trioxide (ATO) is an important agent for the treatment of relapsed and newly diagnosed APL. ATO induces apoptosis, autophagy, and partial cellular differentiation as well as inhibiting cell growth and angiogenesis. Recognition of signaling pathways and molecular mechanisms induced by ATO can be effective for discovering novel treatment strategies to target leukemia cells. Also, it can be developed for the treatment of a variety of cancer cells. This review provides a perspective on anticancerous effects of ATO on APL and leukemia cells.

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Arsenic trioxide induces apoptosis and G2/M phase arrest by inducing Cbl to inhibit PI3K/Akt signaling and thereby regulate p53 activation

Cited by 75 publications

References 30 publications

E3 ubiquitin ligase Cbl-b potentiates the apoptotic action of arsenic trioxide by inhibiting the PI3K/Akt pathway

E3 ubiquitin ligase Cbl-b potentiates the apoptotic action of arsenic trioxide by inhibiting the PI3K/Akt pathway

Role in Chemotherapy

Mechanistic effects of arsenic trioxide on acute promyelocytic leukemia and other types of leukemias

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