Cancerous inhibitor of protein phosphatase 2A determines bortezomib-induced apoptosis in leukemia cells

Liu, Chun Yu; Shiau, Chung Wai; Kuo, Hsin Yu; Huang, Haibo; Chen, Ming-Huang; Tzeng, Cheng Hwai; Chen, Kuen Feng

doi:10.3324/haematol.2011.050187

Cited by 40 publications

(43 citation statements)

References 51 publications

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“…In addition, the high-expression level of CIP2A can elevate the drug resistance to doxorubicin in breast cancer (Vaarala et al, 2010). More importantly, it has been shown that CIP2A was the major molecular target in bortezomibinduced apoptosis in many carcinomas (Liu et al, 2013;Tseng et al, 2012). Taken together, CIP2A plays significant role in human cancers.…”

Section: Discussionmentioning

confidence: 98%

Expression and prognostic significance of CIP2A in cutaneous malignant melanoma

Feng

Ding

et al. 2013

Biomarkers

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Section: Discussionmentioning

confidence: 98%

Expression and prognostic significance of CIP2A in cutaneous malignant melanoma

Feng

Ding

et al. 2013

Biomarkers

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“…Third, a PP2A inhibitor, okadaic acid, significantly reduced the TD-19-induced apoptosis, and a PP2A enhancer, forskolin, increased the apoptotic effect of TD-19 in H460 cells. Taken together, these results indicate that the inhibition of CIP2A and downstream activation of PP2A and inhibition of p-AKT mediated the antitumor effects of TD-19 Huang et al, 2012;Lin et al, 2012;Tseng et al, 2012;Liu et al, 2013;Yu et al, 2013a,b).…”

Section: Discussionmentioning

confidence: 68%

TD-19, an Erlotinib Derivative, Induces Epidermal Growth Factor Receptor Wild-Type Nonsmall-Cell Lung Cancer Apoptosis through CIP2A-Mediated Pathway

Chao¹,

Wang²,

Lai

et al. 2014

J Pharmacol Exp Ther

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Some patients with nonsmall-cell lung cancer (NSCLC) without epidermal growth factor receptor (EGFR) mutations still respond to gefitinib and erlotinib, suggesting that there may be a mechanism(s) other than the EGFR pathway that mediates the tumoricidal effects. In the current study, we tested the efficacy of TD-19, a novel compound chemically modified from erlotinib, which has more potent apoptotic effects than erlotinib in EGFR wild-type NSCLC cell lines. TD-19 induced significant cell death and apoptosis in H358, H441, H460, and A549 cells, as evidenced by increased caspase-3 activity and cleavage of procaspase-9 and poly (ADP-ribose) polymerase. The apoptotic effect of TD-19 in H460 cells, which were resistant to erlotinib, was associated with downregulation of cancerous inhibitor of protein phosphatase 2A (CIP2A), increased protein phosphatase 2A (PP2A) activity, and decreased AKT phosphorylation, but minimal effects on EGFR phosphorylation. Overexpression of CIP2A partially protected the H460 cells from TD-19-induced apoptosis. Okadaic acid, a known PP2A inhibitor, significantly reduced TD-19-induced apoptosis, while forskolin, which increased PP2A activity, increased the apoptotic effect of TD-19. TD-19 inhibited the growth of H460 xenograft tumors by ∼80%. We conclude that TD-19 exerted tumoricidal effects on NSCLC cells. TD-19 provides proof that the CIP2A pathway may be a novel target for the treatment of EGFR wild-type NSCLC.

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“…For assessment of apoptosis (sub-G1) in primary cells, specific cell death was calculated with the formula: (xt-xm/100-xm)/100, where xt was the number of apoptotic cells in response to a given carfilzomib concentration and xm was the apoptotic cells among the untreated cells (Liu et al, 2013). For assessment of apoptosis (sub-G1) in primary cells, specific cell death was calculated with the formula: (xt-xm/100-xm)/100, where xt was the number of apoptotic cells in response to a given carfilzomib concentration and xm was the apoptotic cells among the untreated cells (Liu et al, 2013).…”

Section: Apoptosis Assaymentioning

confidence: 99%

“…Transfection HL-60 cells were transfected with MYC-tagged KIAA1524 as previously described (Liu et al, 2013). KIAA1524 (CIP2A) cDNA was purchased from Origene (Catalogue number RC219918; Rockville, MD, USA) and constructed into the pCMV6 vector.…”

Section: Apoptosis Assaymentioning

confidence: 99%

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Carfilzomib induces leukaemia cell apoptosis via inhibitingELK1/KIAA1524 (Elk‐1/CIP2A) and activatingPP2A not related to proteasome inhibition

et al. 2017

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Enhancing the tumour suppressive activity of protein phosphatase 2A (PP2A) has been suggested to be an anti-leukaemic strategy. KIAA1524 (also termed CIP2A), an oncoprotein inhibiting PP2A, is associated with disease progression in chronic myeloid leukaemia and may be prognostic in cytogenetically normal acute myeloid leukaemia. Here we demonstrated that the selective proteasome inhibitor, carfilzomib, induced apoptosis in sensitive primary leukaemia cells and in sensitive leukaemia cell lines, associated with KIAA1524 protein downregulation, increased PP2A activity and decreased p-Akt, but not with the proteasome inhibition effect of carfilzomib. Ectopic expression of KIAA1524, or pretreatment with the PP2A inhibitor, okadaic acid, suppressed carfilzomib-induced apoptosis and KIAA1524 downregulation in sensitive cells, whereas co-treatment with the PP2A agonist, forskolin, enhanced carfilzomib-induced apoptosis in resistant cells. Mechanistically, carfilzomib affected KIAA1524 transcription through disturbing ELK1 (Elk-1) binding to the KIAA1524 promoter. Moreover, the drug sensitivity and mechanism of carfilzomib in xenograft mouse models correlated well with the effects of carfilzomib on KIAA1524 and p-Akt expression, as well as PP2A activity. Our data disclosed a novel drug mechanism of carfilzomib in leukaemia cells and suggests the potential therapeutic implication of KIAA1524 in leukaemia treatment.

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Cancerous inhibitor of protein phosphatase 2A determines bortezomib-induced apoptosis in leukemia cells

Abstract: ©2013 Ferrata Storti Foundation. This is an open-access paper.

Cited by 40 publications

References 51 publications

Expression and prognostic significance of CIP2A in cutaneous malignant melanoma

Expression and prognostic significance of CIP2A in cutaneous malignant melanoma

TD-19, an Erlotinib Derivative, Induces Epidermal Growth Factor Receptor Wild-Type Nonsmall-Cell Lung Cancer Apoptosis through CIP2A-Mediated Pathway

Carfilzomib induces leukaemia cell apoptosis via inhibitingELK1/KIAA1524 (Elk‐1/CIP2A) and activatingPP2A not related to proteasome inhibition

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