Molecular Determinants of AHPN (CD437)-Induced Growth Arrest and Apoptosis in Human Lung Cancer Cell Lines

Li, Yin; Lin, Bingzhen; Agadir, Anissa; Liu, Ru; Dawson, Marcia I.; Reed, John C.; Fontana, Joseph A.; Bost, Fréd́eric; Hobbs, Peter D.; Zheng, Yun; Chen, Guoquan; Shroot, Braham; Mercola, Dan; Zhang, Xiaokun

doi:10.1128/mcb.18.8.4719

Cited by 162 publications

(190 citation statements)

References 66 publications

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“…In this context, CD437 has been shown to induce growth arrest in G1 28,59,60 or S phase 55,61,62 in a variety of tumor cell lines as well as in normal mammary epithelial cells. We therefore analyzed the effect of MX2870-1 and MX781 on cell cycle progression in Jurkat-Bcl-2 cells.…”

Section: Rrms Induce Cell Cycle Arrest Independently Of the Retinoid mentioning

confidence: 99%

Retinoid-related molecules require caspase 9 for the effective release of Smac and the rapid induction of apoptosis

López-Hernández¹,

Ortiz²,

Bayón³

et al. 2003

Cell Death Differ

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Certain retinoid-related molecules (RRMs) with agonist or antagonist activities have been described to induce apoptosis in a variety of cancer cell lines and show promise for the treatment of cancer. Similar to other chemotherapeutic drugs, these retinoid analogs have been suggested to induce apoptosis through the intrinsic pathway, which requires the release of cytochrome c from the mitochondria for the effective activation of caspase 9. Expression of a catalytically inactive form of caspase 9, which functions as a dominant negative mutant, inhibits the induction of DEVDase activity and nuclear fragmentation by selective RRMs. Whereas the RRMs could induce the release of cytochrome c in the absence of caspase 9 activity, the later is necessary for the effective release of Smac/Diablo from the mitochondria. Furthermore, overexpression of Bcl-2 or Bcl-X L also inhibits RRM-induced apoptosis. We demonstrate that activation of caspase 2 by the agonist MX2870-1 requires caspase 9 activity and is inhibited by Bcl-2 overexpression. In contrast, the antagonist MX781 induces cleavage of procaspase 2 upstream of mitochondria and independently of caspase 9. Thus, two retinoid analogs with unique characteristics activate two distinct apical caspases (2 or 9) to initiate apoptosis. In addition to caspase-mediated cell death, sustained exposure to the RRMs can also lead to loss of cell viability in cells lacking caspase 9 activity or in cells stimulated in the presence of the caspase inhibitor Z-VADfmk. Moreover, MX2870-1 and MX781 produce cell cycle arrest independently of caspase activity and the retinoid receptors.

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Section: Rrms Induce Cell Cycle Arrest Independently Of the Retinoid mentioning

confidence: 99%

Retinoid-related molecules require caspase 9 for the effective release of Smac and the rapid induction of apoptosis

López-Hernández¹,

Ortiz²,

Bayón³

et al. 2003

Cell Death Differ

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“…Nur77 expression is rapidly induced during apoptosis of immature thymocytes, T-cell hybridomas and various cancer cell types (Liu et al, 1994;Woronicz et al, 1994;Li et al, 1998Li et al, , 2000Milbrandt, 1988;Uemura and Chang, 1998). We have previously demonstrated a new paradigm in cancer cell apoptosis, in which Nur77 is induced, then translocates from the nucleus to the mitochondria, leading to release of cytochrome c from the mitochondria (Li et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

et al. 2006

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Proapoptotic nuclear receptor family member Nur77 translocates from the nucleus to the mitochondria, where it interacts with Bcl-2 to trigger apoptosis. Nur77 translocation is induced by certain apoptotic stimuli, including the synthetic retinoid-related 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN)/ CD437 class. In this study, we investigated the molecular mechanism by which AHPN/CD437 analog (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces Nur77 nuclear export. Our results demonstrate that 3-Cl-AHPC effectively activated Jun N-terminal kinase (JNK), which phosphorylates Nur77. Inhibition of JNK activation by a JNK inhibitor suppressed 3-Cl-AHPC-induced Nur77 nuclear export and apoptosis. In addition, several JNK upstream activators, including the phorbol ester TPA, anisomycin and MAPK kinase kinase-1 (MEKK1), phosphorylated Nur77 and induced its nuclear export. However, Nur77 phosphorylation by JNK, although essential, was not sufficient for inducing Nur77 nuclear export. Induction of Nur77 nuclear export by MEKK1 required a prolonged MEKK1 activation and was attenuated by Akt activation. Expression of constitutively active Akt prevented MEKK1-induced Nur77 nuclear export. Conversely, transfection of dominant-negative Akt or treatment with a phosphatidylinositol 3-kinase (PI3-K) inhibitor accelerated MEKK1-induced Nur77 nuclear export. Furthermore, mutation of an Akt phosphorylation residue Ser351 in Nur77 abolished the effect of Akt or the PI3-K inhibitor. Together, our results demonstrate that both activation of JNK and inhibition of Akt play a role in translocation of Nur77 from the nucleus to the cytoplasm.

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“…More recently, CD437-induced apoptosis has been identi®ed to require caspase activation in various cancer cells (Piedra®ta and Pfahl, 1997), including human NSCLC cells (Sun et al, 1999). In addition, CD437-induced apoptosis was also reported to be related to AP-1 activation in human melanoma cells (Schadendorf et al, 1996) and lung cancer cells (Li et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, this retinoid has been identi®ed to be a potent inducer of apoptosis in human lung cancer (Sun et al, 1997b;Adachi et al, 1998;Li et al, 1998), breast cancer (Shao et al, 1995), cervical cancer (Oridate et al, 1997), melanoma (Schadendorf et al, 1996) and leukemia (Hsu et al, 1997) cells. CD437 can selectively bind and activate RARg receptor (Bernard et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Implication of c-Myc in apoptosis induced by the retinoid CD437 in human lung carcinoma cells

et al. 1999

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The novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) has been recently identi®ed to be a potent inducer of apoptosis in human non-small cell lung carcinoma (NSCLC) cells through a nuclear retinoic acid receptor independent mechanism. To approach the mechanism by which CD437 induces apoptosis in NSCLC cells, we investigated the involvement of c-Myc in CD437-induced apoptosis. CD437 (1 mM) up-regulated the expression of c-Myc and of its downstream target genes ornithine decarboxylase (ODC) and cdc25A in all three NSCLC cell lines (i.e., H460, SK-MES-1 and H1792) used. These e ects were correlated with cellular susceptibilities to induction of apoptosis by CD437. Furthermore, CD437-induced apoptosis could be blocked by the ODC inhibitor di¯uoromethylornithine, the caspase inhibitors Z-VAD FMK and Z-DEVD FMK, and cMyc antisense oligodeoxynucleotide, respectively. These data indicate that c-Myc gene plays an important role in mediating CD437-induced apoptosis in human NSCLC cells.

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Molecular Determinants of AHPN (CD437)-Induced Growth Arrest and Apoptosis in Human Lung Cancer Cell Lines

Cited by 162 publications

References 66 publications

Retinoid-related molecules require caspase 9 for the effective release of Smac and the rapid induction of apoptosis

Retinoid-related molecules require caspase 9 for the effective release of Smac and the rapid induction of apoptosis

Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

Implication of c-Myc in apoptosis induced by the retinoid CD437 in human lung carcinoma cells

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