Apoptosis and inactivation of the PI3-kinase pathway by tetrocarcin A in breast cancers

Nakajima, Hiroo; Sakaguchi, Kôichi; Fujiwara, Ikuya; Mizuta, Mitsuhiko; Tsuruga, Mie; Magae, Junji; Mizuta, Naruhiko

doi:10.1016/j.bbrc.2007.02.136

Cited by 28 publications

(23 citation statements)

References 36 publications

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“…Of the six synergistic TRAIL sensitizers, it is interesting to note that five are reported to target DNA and/or RNA in one manner or another: antibiotic M259 (DNA and RNA synthesis inhibition) [53], cyanocycline A (DNA and RNA synthesis inhibition; DNA-binding) [19, 20], mithramycin A (DNA fragmentation; DNA minor groove binding) [27, 28], 23,24-dihydrocucurbitacin B (closely related to cucurbitacin B; causes DNA fragmentation) [72] and tetrocarcin A (DNA synthesis inhibition; DNA fragmentation) [36, 39], suggesting that nucleic acid oxidation-, damage-, or synthesis-sensing mechanisms may feed into the TRAIL signaling pathway at early time points. This insight may lead to further exploration of pathways involving RNA/DNA synthesis inhibition, reactive oxygen species generation, p53, p21, and CDK regulation and their potential interaction(s) with the TRAIL death receptor signaling system.…”

Section: Discussionmentioning

confidence: 99%

A cell-based high-throughput screen to identify synergistic TRAIL sensitizers

Booth

Sayers

Brooks

et al. 2008

Cancer Immunol Immunother

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We have developed a high-throughput screen (HTS) to search for novel molecules that can synergize with TRAIL, thus promoting apoptosis of ACHN renal tumor cells in a combinatorial fashion. The HTS detects synthetic compounds and pure natural products that can pre-sensitize the cancer cells to TRAIL-mediated apoptosis, yet have limited toxicity on their own. We have taken into account the individual effects of the single agents, versus the combination, and have identified hits that are synergistic, synergistic-toxic, or additive when combined with TRAIL in promoting tumor cell death. Preliminary mechanistic studies indicate that a subset of the synergistic TRAIL sensitizers act very rapidly to promote cleavage and activation of caspase-8 following TRAIL binding. Caspase-8 is an apical enzyme that initiates programmed cell death via the extrinsic apoptotic pathway. Thus, these TRAIL sensitizers may potentially reduce resistance of tumor cells to TRAIL-mediated apoptosis. Two representative sensitizers were found to increase levels of p53 but did not inhibit the proteasome, suggesting that early DNA damage-sensing pathways may be involved in their mechanisms of action.

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Section: Discussionmentioning

confidence: 99%

A cell-based high-throughput screen to identify synergistic TRAIL sensitizers

Booth

Sayers

Brooks

et al. 2008

Cancer Immunol Immunother

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“…To furnish the molecule, tetronolide has two sugar side chains appended, a tetrasaccharide unit that comprises alternate L-digitoxoses and L-amicetoses and 2,3,4,6-tetradeoxy-4-(methylcarbamoyl)-3-C-methyl-3-nitro-D-xylo-hexopyranose, a rare deoxynitrosugar also known as D-tetronitrose or D-kijanose in kijanimicin (KIJ) (21,39). Intriguingly, recent studies have demonstrated that TCA can induce apoptosis of various tumor cells in a cell-type-dependent manner, e.g., by (i) antagonizing the mitochondrial functions of proteins of the Bcl-2 family (natural apoptosis inhibitors) in HeLa cells (8,26), (ii) activating the caspase-dependent cell death pathway via endoplasmic reticulum stress in lymphomas (1,41), and (iii) inhibiting the phosphorylation of factors involved in phosphatidylinositol 3-kinase/Akt signaling in human breast cancer cells (25). Synthetic TCA analogs that showed the separable antibacterial and antitumor activities also supported the versatile modes of action of TCA in vivo (12).…”

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confidence: 99%

Cloning and Characterization of the Tetrocarcin A Gene Cluster from Micromonospora chalcea NRRL 11289 Reveals a Highly Conserved Strategy for Tetronate Biosynthesis in Spirotetronate Antibiotics

et al. 2008

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Tetrocarcin A (TCA), produced by Micromonospora chalcea NRRL 11289, is a spirotetronate antibiotic with potent antitumor activity and versatile modes of action. In this study, the biosynthetic gene cluster of TCA was cloned and localized to a 108-kb contiguous DNA region. In silico sequence analysis revealed 36 putative genes that constitute this cluster (including 11 for unusual sugar biosynthesis, 13 for aglycone formation, and 4 for glycosylations) and allowed us to propose the biosynthetic pathway of TCA. The formation of D-tetronitrose, L-amicetose, and L-digitoxose may begin with D-glucose-1-phosphate, share early enzymatic steps, and branch into different pathways by competitive actions of specific enzymes. Tetronolide biosynthesis involves the incorporation of a 3-C unit with a polyketide intermediate to form the characteristic spirotetronate moiety and trans-decalin system. Further substitution of tetronolide with five deoxysugars (one being a deoxynitrosugar) was likely due to the activities of four glycosyltransferases. In vitro characterization of the first enzymatic step by utilization of 1,3-biphosphoglycerate as the substrate and in vivo cross-complementation of the bifunctional fused gene tcaD3 (with the functions of chlD3 and chlD4) to ⌬chlD3 and ⌬chlD4 in chlorothricin biosynthesis supported the highly conserved tetronate biosynthetic strategy in the spirotetronate family. Deletion of a large DNA fragment encoding polyketide synthases resulted in a non-TCA-producing strain, providing a clear background for the identification of novel analogs. These findings provide insights into spirotetronate biosynthesis and demonstrate that combinatorial-biosynthesis methods can be applied to the TCA biosynthetic machinery to generate structural diversity.

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“…Cytoplasmic kinases are intracellular messengers that play an important role in signal transduction. Thus, we examined the effects of HEK293 cells expressing wtRON or RONΔ165 E2 on two common downstream pathways, PI3K/AKT and MAPK, in the presence or absence of MSP [10, 26–33]. To our surprise, in HEK293 RONΔ165 E2 cells, the PI3K/AKT/mTOR pathway was significantly activated, whereas the MAPK pathway was significantly inhibited.…”

Section: Discussionmentioning

confidence: 99%

A novel RON splice variant lacking exon 2 activates the PI3K/AKT pathway via PTEN phosphorylation in colorectal carcinoma cells

Kuang

Chen

et al. 2017

Oncotarget

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Abnormal expression of the Recepteur d'Origine Nantais (RON) receptor tyrosine kinase is accompanied by the generation of multiple splice or truncated variants, which mediate many critical cellular functions that contribute to tumor progression and metastasis. Here, we report a new RON splice variant in the human colorectal cancer (CRC) cell line HT29. This variant is a 165 kda protein generated by alternative pre-mRNA splicing that eliminates exon 2, causing an in-frame deletion of 63 amino acids in the extracellular domain of the RON β chain. The deleted transcript was a single chain expressed in the intracellular compartment. Although it lacked tyrosine phosphorylation activity, the RONΔ165E2 variant could phosphorylate phosphatase and tensin homolog (PTEN), thereby activating the PI3K/AKT pathway. In addition, in vitro and in vivo experiments showed that the RONΔ165E2 promoted cell migration and tumor growth. Finally, in an investigation of 67 clinical CRC samples, the variant was highly expressed in about 58% of the samples, and was positively correlated with the invasive depth of the tumor (P < 0.05). These results demonstrate that the novel RONΔ165E2 variant promoted tumor progression while activating the PI3K/AKT pathway via PTEN phosphorylation.

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Apoptosis and inactivation of the PI3-kinase pathway by tetrocarcin A in breast cancers

Cited by 28 publications

References 36 publications

A cell-based high-throughput screen to identify synergistic TRAIL sensitizers

A cell-based high-throughput screen to identify synergistic TRAIL sensitizers

Cloning and Characterization of the Tetrocarcin A Gene Cluster from Micromonospora chalcea NRRL 11289 Reveals a Highly Conserved Strategy for Tetronate Biosynthesis in Spirotetronate Antibiotics

A novel RON splice variant lacking exon 2 activates the PI3K/AKT pathway via PTEN phosphorylation in colorectal carcinoma cells

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