Inhibition of autophagy induced by overexpression of mda-7/interleukin-24 strongly augments the antileukemia activity in vitro and in vivo

Yang, Chunmei; Yin, Tong; Ni, Wangmao; Liu, Jian; Xu, Wenxia; Li, L; Liu, Xueqin; Meng, Haitao; Qian, W.

doi:10.1038/cgt.2009.57

Cited by 31 publications

(33 citation statements)

References 53 publications

(66 reference statements)

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“…On the other hand, stable transfection of chronic myeloid leukemia cells (K562) or Nawalma lymphoma cells with MDA-7/IL-24 inhibited cell growth without inducing apoptosis (Dong et al, 2008). In this context, recent studies suggest that the ability of enforced expression of adenoviral mda-7/IL-24 to induce apoptosis in leukemia cells is attenuated by autophagy (Yang et al, 2010). Regardless of the mechanisms responsible for these discrepancies, our findings indicate that diverse human myeloid leukemia cells are highly sensitive to GST-MDA-7/IL-24-mediated apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Melanoma Differentiation Associated Gene-7/Interleukin-24 Potently Induces Apoptosis in Human Myeloid Leukemia Cells through a Process Regulated by Endoplasmic Reticulum Stress

Rahmani

Mayo²,

Dash³

et al. 2010

Mol Pharmacol

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Melanoma differentiation associated gene-7 (mda-7)/interleukin-24 (IL-24), a member of the IL-10 cytokine gene family, preferentially induces cell death in neoplastic epithelial cells types while sparing their normal counterparts. The effects of mda-7/ IL-24 in acute myeloid leukemia (AML) cells have not been extensively characterized. Treatment with recombinant GST-MDA-7/ IL-24 potently induced apoptosis in diverse myeloid leukemia cell types including U937, HL60, MV4-11, EOL-1, and MLL/ENL cells. MDA-7/IL-24 also markedly induced apoptosis in and suppressed the colony-forming capacity of primary AML blasts but exerted minimal toxicity toward normal CD34 ϩ hematopoietic progenitor cells. MDA-7/IL-24 lethality was associated with pronounced endoplasmic reticulum (ER) stress induction in leukemia cell lines and primary AML blasts, manifested by the accumulation of growth arrest and DNA damage-inducible protein 34 (GADD34), 78-kDa glucose-regulated protein (GRP78)/BiP, inositol-requiring enzyme 1␣ (IRE1␣), and eukaryotic initiation factor 2␣ phosphorylation. It is noteworthy that short hairpin RNA (shRNA) knockdown of IRE1␣, GADD34, or GRP78/BiP significantly enhanced MDA-7/IL-24-mediated apoptosis, indicating a protective role for these molecules against MDA-7/IL-24 lethality. MDA-7/IL-24 also down-regulated the antiapoptotic protein Mcl-1 and sharply increased expression of the proapoptotic proteins Bim and Noxa. Ectopic Mcl-1 expression or shRNA knockdown of Bim or Noxa significantly attenuated MDA-7/IL-24-mediated leukemia cell death. Finally, knockdown of Bax or Bak significantly reduced MDA-7/IL-24 lethality. Together, these findings indicate that MDA-7/IL-24 potently induces apoptosis in human myeloid leukemia cells through a process regulated by ER stress induction, Mcl-1 down-regulation, and Bim and Noxa up-regulation. They also suggest that MDA-7/IL-24 warrants further investigation in myeloid leukemia.

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Section: Discussionmentioning

confidence: 99%

Melanoma Differentiation Associated Gene-7/Interleukin-24 Potently Induces Apoptosis in Human Myeloid Leukemia Cells through a Process Regulated by Endoplasmic Reticulum Stress

Rahmani

Mayo²,

Dash³

et al. 2010

Mol Pharmacol

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“…In mda-7/IL-24 leukemia models, for example, inhibition of autophagy by the PtdIns3K inhibitor wortmannin results in reduced Beclin 1 expression and is associated with significantly enhanced cell death. 41 Compromising autophagy by Beclin 1 inhibition or siRNA greatly increases the cytotoxicity of the antiestrogen 4-hydroxytamoxifen in breast cancer cells. 42 However, the opposite reaction of Beclin 1 to tumor therapy was also detected.…”

Section: Patients and Materialsmentioning

confidence: 99%

Elevated Beclin 1 expression is correlated with HIF-1α in predicting poor prognosis of nasopharyngeal carcinoma

Wan¹,

Fan²,

Chen³

et al. 2010

Autophagy

123

110

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“…Western blot analysis was performed as described previously [35] , with equal protein loading on 12% SDS-PAGE. The primary antibodies used were caspase-3, poly (ADP-ribose) polymerase (PARP), NF-κB p65, and Phosphor-NF-κB p65 (Ser536), all purchased from Cell Signaling Technology.…”

Section: Wwwchinapharcom Meng Ht Et Almentioning

confidence: 99%

Triptolide inhibits the proliferation of cells from lymphocytic leukemic cell lines in association with downregulation of NF-κB activity and miR-16-1*

Meng

Zhu

et al. 2011

Acta Pharmacol Sin

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Aim: To examine the effects of triptolide (TPL) on T-cell leukemia cells and identify their underlying mechanisms. Methods: The cytotoxicity of TPL was assessed by MTT assay. Cell apoptosis was determined using annexin V and DAPI staining and analyzed by flow cytometry or fluorescence microscopy. The activation of caspase pathways and the expression of nuclear factor κB (NF-κB) p65 were examined by Western blotting. Differences in microRNA (miRNA) expression in Molt-4 and Jurkat cells before and after TPL treatment were identified using microarrays and real-time RT-PCR, respectively. Results: TPL 20−160 nmol/L treatment potently inhibited cell growth and induced apoptosis in T-cell lymphocytic leukemia cell lines. Molt-4 and Jurkat cells, however, were more sensitive to TPL than L428 and Raji cells. After 24 h of treatment, bortezomib abrogated the growth of Molt-4 and Jurkat cells with an IC 50 of 15.25 and 24.68 nmol/L, respectively. Using Molt-4 cells, we demonstrated that TPL 20−80 nmol/L inhibited the translocation of NF-κB p65 from the cytoplasm to the nucleus and that phosphorylated NF-κB p65 in nuclear extracts was down-regulated in a dose-dependent manner. Similar results were also seen in Jurkat cells but not in L428 cells, as these cells are resistant to TPL and bortezomib (a NF-κB inhibitor). Twenty-three miRNAs were differentially expressed after TPL treatment. Functional analysis revealed that TPL treatment could inhibit expression of miR-16-1* and that transfection of miR-16-1* led to significantly decreased apoptosis induced by TPL. Conclusion: Our in vitro studies suggest that TPL might be an effective therapeutic agent for treatment of T-cell lymphocytic leukemia and that its cytotoxic effects could be associated with inhibition of NF-κB and down-regulation of miR-16-1*.

show abstract

Inhibition of autophagy induced by overexpression of mda-7/interleukin-24 strongly augments the antileukemia activity in vitro and in vivo

Cited by 31 publications

References 53 publications

Melanoma Differentiation Associated Gene-7/Interleukin-24 Potently Induces Apoptosis in Human Myeloid Leukemia Cells through a Process Regulated by Endoplasmic Reticulum Stress

Melanoma Differentiation Associated Gene-7/Interleukin-24 Potently Induces Apoptosis in Human Myeloid Leukemia Cells through a Process Regulated by Endoplasmic Reticulum Stress

Elevated Beclin 1 expression is correlated with HIF-1α in predicting poor prognosis of nasopharyngeal carcinoma

Triptolide inhibits the proliferation of cells from lymphocytic leukemic cell lines in association with downregulation of NF-κB activity and miR-16-1*

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