Visualization and Quantitative Analysis of Embryonic Angiogenesis in <em>Xenopus tropicalis</em>

Blood vessels supply oxygen and nutrients throughout the body, and the formation of the vascular network is under tight developmental control. The ...

Yonsei University College of Medicine

Angelica genus (umbelliferae) has traditionally been used as the medicine and health food considered alleviating several used in the treatment of cancer as well as non-cancerous diseases. Angelica purpuraefolia Chung is an endemic species and a folk medicine in Korea. We have previously reported that two natural khellactone isolated from the rhizomes of A. purpuraefolia has significant antiplasmodial activity against Plasmodium falciparum. In the present study, we scientifically evaluated the effect of (+)-4'-decanoyl-cis-khellactone and (+)-3'-decanoyl-cis-khellactone from A. purpuraefolia on cell proliferation and apoptotic cell death. The anti-proliferative and apoptotic effects of (+)-4'-decanoyl-cis-khellactone and (+)-3'-decanoyl-cis-khellactone (10-50 μg/ml) were subjected to in vitro evaluation using four breast (MDA-MB-231, MCF-7, HS578T, and T47D), three cervical (HeLa, SiHa, and C33A) cancer cell lines, and NIH 3T3 normal cells using FACS and western analyses. Our in vitro experiments showed that (+)-4'-decanoyl-cis-khellactone and (+)-3'-decanoyl-cis-khellactone suppress the growth and proliferation of cancer cells at a relatively low concentration (<10 μg/ml) and induce apoptosis at a high concentration (>50 μg/ml). FACS analysis showed that the cell cycle arrest in the S/G2 phase was induced by the treatment with 10 μg/ml of (+)-4'-decanoyl-cis-khellactone and (+)-3'-decanoyl-cis-khellactone in MDA-MB-231 cells. Western blot analysis also showed that concentration higher than 50 μg/ml of (+)-4'-decanoyl-cis-khellactone induced a time-dependent increase in the percentage of apoptotic cells. However, our results showed that (+)-4'-decanoyl-cis-khellactone uses both extrinsic and intrinsic pathways but (+)-3'-decanoyl-cis-khellactone uses only an intrinsic pathway for the apoptosis. More importantly, (+)-4'-decanoyl-cis-khellactone and (+)-3'-decanoyl-cis-khellactone inhibited the in vitro proliferation of six other human breast and cervical cancer cell lines. Our data strongly suggest that (+)-4'-decanoyl-cis-khellactone and (+)-3'-decanoyl-cis-khellactone act as an anti-cancer supplement particularly against breast and cervical cancers by inducing cell cycle arrest in the S/G2 phase and caspase-dependent apoptosis at relatively low and high concentrations, respectively.

Inhibitory effect and mechanism on antiproliferation of khellactone derivatives from herbal suitable for medical or food uses.

Paulownia coreana has traditionally been used as the medicine and health food in the treatment of cancer and infectious diseases. In the present study, a new antiproliferation agent, isoatriplicolide tiglate (PCAC) was isolated from the chloroform soluble fraction of the leaves of Paulownia coreana. The antiproliferation activities of PCAC plant extract was examined in breast and cervical cancer cell lines in a time-and dose-dependent manners. Our in vitro experiments showed that PCAC suppresses the cell growth and proliferation of cancer cells at a relatively low concentration (< 10 µg/mL) and induces apoptosis at a high concentration (> 50 µg/mL). Western blot analysis showed that concentration higher than 50 µg/mL induces a time-dependent increase in the percentage of apoptotic cells. In this case, PCAC uses both extrinsic and intrinsic pathways for the apoptosis. PCAC treatment decreased the expression of pro-caspase 8, 9, and 3, the main regulators of apoptotic cell death, in MDA-MB-231 cells, accompanied by the activation of caspase 8, 9, and 3. More importantly, PCAC inhibited the in vitro proliferation of six other human breast and cervical cancer cell lines. In conclusion, our data strongly suggest that PCAC acts as an antiproliferation agents particularly against breast and cervical cancers by inducing cell cycle arrest in the S/G2 phase and caspase dependent apoptosis at relatively low (< 10 μg/mL) and high (> 50 µg/mL) concentrations, respectively.

Inhibitory effect and mechanism on antiproliferation of isoatriplicolide tiglate (PCAC) from Paulownia Coreana.

A 34-KD protein encoded by the SEI-1 gene (p34(SEI‑1)), is a relatively recently discovered oncoprotein that has multiple important biological functions. Our data show that p34(SEI-1) enhances cancer cell survival and promotes tumorigenesis by downregulating the tumor suppressor PTEN, a negative regulator of the PI3K/AKT signaling pathway, and therefore activating the PI3K/AKT signaling pathway. In this process, p34(SEI-1) positively affects NEDD4-1 gene expression both at the transcriptional and protein levels. Furthermore, the expression levels of p34(SEI-1) and NEDD4-1 were found to be coordinated in tumor tissues obtained from patients with breast cancer. We also show that p34(SEI-1) affects the subcellular localization of PTEN.

Oncogenic function of p34SEI-1 via NEDD4‑1‑mediated PTEN ubiquitination/degradation and activation of the PI3K/AKT pathway.

The p34(SEI-1) oncoprotein is involved in a transcriptional regulation, cell cycle regulation, apoptosis, development and many other important cellular functions. Our present study suggests that p34(SEI-1) can promote metastasis by enhancing migration and invasion of cancer cells. Consistently, p34(SEI-1) expression was found to be increased as the tumor invasiveness progressed in human breast tissues. p34(SEI-1) may promote cancer metastasis by activating the PI3K/AKT signaling pathway. In this process, p34(SEI-1) activates two different serine/threonine kinases, AKT or ILK, depending on the expression status of HER2/neu oncogene. In HER2/neu suppressed cancer cells, p34(SEI-1) promoted metastasis mainly by activating AKT via phosphorylation of the 473 serine residue. In HER2/neu expressing cancer cells, p34(SEI-1) overexpression downregulates HER2/neu expression, leading to the activation of another crucial serine/threonine kinase ILK due to phosphorylation of the 178 threonine residue instead of AKT. These results suggest that p34(SEI-1) affects cancer metastasis by regulating two different signaling pathways depending on the HER2/neu expression level, in which AKT and ILK modulation can be stimulated by p34(SEI-1) overexpression.

Distinct regulatory effect of the p34SEI-1 oncoprotein on cancer metastasis in HER2/neu-positive and -negative cells.

Angiogenesis, the process of building complex vascular structures, begins with sprout formation on preexisting blood vessels, followed by extension of the vessels through proliferation and migration of endothelial cells. Based on the potential therapeutic benefits of preventing angiogenesis in pathological conditions, many studies have focused on the mechanisms of its initiation as well as control. However, how the extension of vessels is terminated remains obscure. Thus, we investigated the negative regulation mechanism.

Calmodulin Mediates Ca2+-Dependent Inhibition of Tie2 Signaling and Acts as a Developmental Brake During Embryonic Angiogenesis.

Local mRNA translation mediates the adaptive responses of axons to extrinsic signals, but direct evidence that it occurs in mammalian CNS axons in vivo is scant. We developed an axon-TRAP-RiboTag approach in mouse that allows deep-sequencing analysis of ribosome-bound mRNAs in the retinal ganglion cell axons of the developing and adult retinotectal projection in vivo. The embryonic-to-postnatal axonal translatome comprises an evolving subset of enriched genes with axon-specific roles, suggesting distinct steps in axon wiring, such as elongation, pruning, and synaptogenesis. Adult axons, remarkably, have a complex translatome with strong links to axon survival, neurotransmission, and neurodegenerative disease. Translationally co-regulated mRNA subsets share common upstream regulators, and sequence elements generated by alternative splicing promote axonal mRNA translation. Our results indicate that intricate regulation of compartment-specific mRNA translation in mammalian CNS axons supports the formation and maintenance of neural circuits in vivo.

Jiyeon Ohk

Brain Korea 21 PLUS Project for Medical Science

Yonsei University College of Medicine

Visualization and Quantitative Analysis of Embryonic Angiogenesis in Xenopus tropicalis

Jiyeon Ohk

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Yonsei University College of Medicine

Visualization and Quantitative Analysis of Embryonic Angiogenesis in Xenopus tropicalis

Brain Korea 21 PLUS Project for Medical Science