• 한국식품영양과학회지
• /
• 제32권3호
• /
• pp.428-436
• /
• 2003

Carotenoids는 항암 효과가 있는 것으로 알려져 있으나 각각의 carotenoids가 대장암에 미치는 영향에 대해서는 명확하게 밝혀진 바가 없다. 본 연구에서는 4가지 종류의 carotenoids가 인간의 대장에서 유래한 암세포인 HT-29 세포의 증식에 미치는 영향을 조사하였다. $\alpha$-carotene, $\beta$-carotene, lutein lycopene을 농도를 달리 하여 세포 배양액 에 첨가하여 살아있는 세포의 수를 측정한 결과 $\beta$-carotene는 세포의 증식을 다소 증가시키는 반면 $\alpha$-carotene, lutein, lcopene은 세포의 증식을 감소하였다. 세포의 증식을 억제한 carotenoids 중에서 lycopene이 그 효과가 가장 컸다. ErbB receptor family는 세포의 증식을 촉진하고 대장암에서 그 발현이 증가된 것으로 보고되었기 때문에 lycopene이 heregulin-ErbB3 signaling을 억제하는지를 조사하였다. Lycopene는 ErbB2 단백질을 감소하였고 ErbB3 단백질의 변화를 초래하였다. Heregulin을 첨가하여 인산화를 유도한 경우 ErbB3의 인산화, ErbB3와 p85의 결합, Akt 인산화가 lycopene에 의해 억제되었다. 이 결과들은 carotenoids 중 lycopene이 대장암 세포 증식 억제 효과가 가장 크고, 대장암 세포의 DNA 합성을 억제하고 apoptosis를 유도하는 lycopene효과의 일부는 Erb-B3와 Akt의 인산화 감소에 기인하는 것임을 나타낸다.

• Biomolecules & Therapeutics
• /
• 제30권3호
• /
• pp.274-283
• /
• 2022

KRAS activating mutations, which are present in more than 90% of pancreatic cancers, drive tumor dependency on the RAS/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. Therefore, combined targeting of RAS/MAPK and PI3K/AKT signaling pathways may be required for optimal therapeutic effect in pancreatic cancer. However, the therapeutic efficacy of combined MAPK and PI3K/AKT signaling target inhibitors is unsatisfactory in pancreatic cancer treatment, because it is often accompanied by MAPK pathway reactivation by PI3K/AKT inhibitor. Therefore, we developed an inRas37 antibody, which directly targets the intra-cellularly activated GTP-bound form of oncogenic RAS mutation and investigated its synergistic effect in the presence of the PI3K inhibitor BEZ-235 in pancreatic cancer. In this study, inRas37 remarkably increased the drug response of BEZ-235 to pancreatic cancer cells by inhibiting MAPK reactivation. Moreover, the co-treatment synergistically inhibited cell proliferation, migration, and invasion and exhibited synergistic anticancer activity by inhibiting the MAPK and PI3K pathways. The combined administration of inRas37and BEZ-235 significantly inhibited tumor growth in mouse models. Our results demonstrated that inRas37 synergistically increased the antitumor activity of BEZ-235 by inhibiting MAPK reactivation, suggesting that inRas37 and BEZ-235 co-treatment could be a potential treatment approach for pancreatic cancer patients with KRAS mutations.

• 생명과학회지
• /
• 제21권9호
• /
• pp.1234-1243
• /
• 2011

맥문동(Liriope platyphylla)은 동양의학에서 오래 동안 항염증제, 당뇨 혹은 비만 치료제, 그리고 신경세포활성화 약제로 사용되어 왔다. 본 연구에서는 맥문동으로부터 NGF의 발현을 촉진하는 새로운 물질을 개발하고 이들의 작용기전을 밝히기 위하여 맥문동으로부터 13가지의 새로운 추출물을 확보하고 이들의 기능을 세포주와 마우스 실험을 통해 분석하였다. 그 결과, 상대적으로 세포독성이 낮고 NGF의 분비량이 많은 LP-E, LP-M, LP-M50, LP2E17PJ 등 4가지 추출물을 확보하였다. 또한 이들 중에서 LP2E17PJ를 제외한 3가지 추출물에 의해 분비된 NGF는 PC12세포의 neuritic outgrowth를 촉진하였다. 더불어 추출방법과 추출량의 측면에서 효과적인 LP-M을 C57BL/6 마우스에 2주간 투여하여 뇌조직에서 NGF mRNA의 발현을 확인하였다. LP-M은 오직 피질에서만 두 종류의 receptor 중에서 low affinity receptor를 통한 억제신호를 전달하였으며, 해마에서는 유의적인 변화를 유도하지 못했다. 그러나 high affinity receptor를 통한 신호전달은 해마에서만 활성화 신호를 전달하였고 피질에서는 변화를 유도하지 못했다. 이러한 결과는 맥문동 추출물인 LP-M은 마우스 대뇌의 해마에서 high affinity receptor를 통한 신호전달을 통해 neuritic outgrowth를 촉진함을 확인하였다.

• 생약학회지
• /
• 제52권4호
• /
• pp.234-241
• /
• 2021

Dermal papilla cells (DPCs) are present throughout the hair cycle and play an essential role in hair cycle and hair growth. In this study, we investigated the effect of Carex dispalata on the activation of anagen pathway in DPCs. C. dispalata extract increased the proliferation of DPCs and induced changes in the levels of cell cycle-related proteins. To elucidate the mechanism by which C. dispalata extract stimulates the anagen pathway related to the proliferation of DPCs, we evaluated the effect of C. dispalata extract on the activation of Akt signaling. The increase in the level of phospho-Akt by C. dispalata extract was inhibited by PI3K inhibitor (wortmannin). Wortmannin reduced the effects of C. dispalata extract on the levels of cell cycle-related proteins and proliferation of DPCs. C. dispalata extract increased the levels of Wnt/β-catenin proteins. Wnt/β-catenin inhibitor (XAV939) inhibited changes in cell cycle, cell cycle-related proteins, Wnt/β-catenin proteins, and proliferation induced by C. dispalata extract. C. dispalata extract increased the level of autophagy protein (LC3I/II), and this change was inhibited by XAV939. These results suggest that C. dispalata extract can activate PI3K/Akt, Wnt/β-catenin, and autophagy pathways in DPCs to induce cell proliferation, and thereby promote hair growth phase.

• 생명과학회지
• /
• 제31권3호
• /
• pp.321-329
• /
• 2021

본 연구에서는 매실 메탄올 추출물(maesil methanol fraction, MMF)을 제조하여 인체 전립선암세포 LNCaP, RC-58T 및 PC-3에 대한 증식억제 효과를 확인하였다. 인체 전립선암세포인 PC-3 및 RC-58T와 비교해보았을 때, LNCaP은 MMF의 처리에 따른 증식억제 효과에 가장 민감했다. LNCaP의 형태학적 관찰과 apoptotic body 형성을 관찰해보았으며, MMF의 처리로 인한 형태의 변화, 핵 손상 및 응축을 확인했다. MMF의 처리로 인한 인체 전립선암세포 LNCaP에서 성장억제 효과가 내인성 apoptosis 경로와 관련 있는지 확인한 결과, pro-apoptotic 단백질인 Bax, caspase-3, caspase-9, PARP의 발현이 증가하였고, anti-apoptotic 단백질인 Bcl-2의 발현이 감소하는 것을 확인했다. MMF와 AIF inhibitor인 N-phenylmalemide (N-PM)의 병용처리군에 비해 MMF 단독처리군의 증식억제 효과가 유의적으로 나타났으며 AIF 및 Endo G의 발현 증가를 통해 외인성 apoptosis 경로에 영향을 미치는 것을 확인했다. 또한 PI3K inhibitor인 LY294002와 MMF의 병용처리군에 비해 MMF 단독처리군의 증식억제 효과가 유의적으로 나타났으며 PI3K, p-Akt, p-mTOR의 발현 감소를 통해 PI3K/Akt/mTOR 신호경로에 영향을 미치는 것을 확인했다. 결론적으로 인체 전립선암세포 LNCaP에서 MMF의 증식억제 효과는 천연물 유래 기능성 식품의 소재로써의 가능성을 보여준다.

• Journal of Applied Biological Chemistry
• /
• 제65권4호
• /
• pp.463-469
• /
• 2022

Cudrania tricuspidata (C. tricuspidata), a medicinal plant widely employed throughout Asia in ethnomedicine, has various bioactive properties, including antidiabetic, antiobesity, antitumor, and anti-inflammatory activities. In addition, the C. tricuspidata root extract reportedly inhibits platelet aggregation. Therefore, we focused on the active substances present in the C. tricuspidata extract. Sanggenon N (SN) is a flavonoid found in the root bark of C. tricuspidata. In the present study, we examined the inhibitory effects of SN on platelet aggregation, phosphoproteins, thromboxane A₂ generation, and integrin αIIbβ3 activity. SN inhibited collagen-induced human platelet aggregation in a dose-dependent manner without cytotoxicity. Furthermore, SN suppressed Ca²⁺ mobilization and influx through associated signaling molecules, such as inositol 1, 4, 5-triphosphate receptor I (Ser¹⁷⁵⁶), and extracellular signal-regulated kinase. In addition, SN inhibited thromboxane A₂ generation and associated signaling molecules, including cytosolic phospholipase A₂ and mitogen-activated protein kinase p38. Finally, SN could inhibit integrin (αIIb/β₃) activity by regulating vasodilator-stimulated phosphoprotein and Akt. Collectively, SN possesses potent antiplatelet effects and is a potential therapeutic drug candidate to prevent platelet-related thrombosis and cardiovascular disease.

• IMMUNE NETWORK
• /
• 제20권5호
• /
• pp.36.1-36.13
• /
• 2020

Hippo signaling pathways are evolutionarily conserved signal transduction mechanisms mainly involved in organ size control, tissue regeneration, and tumor suppression. However, in mammals, the primary role of Hippo signaling seems to be regulation of immunity. As such, humans with null mutations in STK4 (mammalian homologue of Drosophila Hippo; also known as MST1) suffer from recurrent infections and autoimmune symptoms. Although dysregulated T cell homeostasis and functions have been identified in MST1-deficient human patients and mouse models, detailed cellular and molecular bases of the immune dysfunction remain to be elucidated. Although the canonical Hippo signaling pathway involves transcriptional co-activator Yes-associated protein (YAP) or transcriptional coactivator with PDZ motif (TAZ), the major Hippo downstream signaling pathways in T cells are YAP/TAZ-independent and they widely differ between T cell subsets. Here we will review Hippo signaling mechanisms in T cell immunity and describe their implications for immune defects found in MST1-deficient patients and animals. Further, we propose that mutual inhibition of Mst and Akt kinases and their opposing roles on the stability and function of forkhead box O and β-catenin may explain various immune defects discovered in mutant mice lacking Hippo signaling components. Understanding these diverse Hippo signaling pathways and their interplay with other evolutionarily-conserved signaling components in T cells may uncover molecular targets relevant to vaccination, autoimmune diseases, and cancer immunotherapies.

• 생명과학회지
• /
• 제34권2호
• /
• pp.94-104
• /
• 2024

β-lapachone은 다양한 유형의 질병을 치료하기 위해 남미 및 중미 지역의 전통 의학에서 널리 사용되어 온 Tabebuia vellanedae의 껍질에서 분리된 천연 퀴논 화합물의 일종이다. β-lapachone은 여러 유형의 암세포에서 강력한 항암 활성을 갖는 것으로 보고되었지만, 간세포암종 세포의 증식에 대한 효과는 아직 불분명하다. 따라서 본 연구에서는 β-lapachone 인간 간세포암종 Hep3B 세포의 증식에 미치는 영향을 조사하였으며, 본 연구의 결과에 의하면, β-lapachone 처리에 의한 Hep3B 세포의 세포생존율 감소는 세포사멸 유도와 밀접한 관련이 있었다. 또한, β-lapachone이 처리된 Hep3B 세포에서는 항세포사멸 인자인 Bcl-2의 발현이 감소한 반면, 세포사멸 유도 인자인 Bax의 발현은 증가하였으며, 이는 caspase cascade의 활성 증가와 연관성이 있었다. 그러나 pan-caspase 억제제가 존재하는 경우 β-lapachone에 의해 유발된 세포사멸은 약화되었으며, 이는 β-lapachone에 의한 세포사멸 유도가 caspase 의존적인 현상임을 의미한다. 아울러, β-lapachone의 처리는 ERK 경로를 활성화시키면서 PI3K/Akt 경로의 활성을 억제하였으며, β-lapachone 유도 세포사멸에 ERK 억제제의 효과는 미미했지만, PI3K 억제제는 β-lapachone에 의해 유도된 세포사멸을 유의하게 증가시켰다. 비록 생체 내 동물 모델에서의 확인이 필요하지만, 본 연구의 결과는 간세포암종 세포에서 β-lapa-chone의 항암 활성을 이해하는 데 유용한 자료로 활용될 것이다.

• BMB Reports
• /
• 제42권9호
• /
• pp.599-604
• /
• 2009

Selenium possesses the chemotherapeutic feature by inducing apoptosis in cancer cell with trivial side effects on normal cells. However, the mechanism in which is not clearly understood. Emerging evidence indicates the overlaps between the autophagy and the apoptosis. In this study, we have investigated the role of autophagy in selenium-induced apoptosis in NB4 cells. We find that autophagy is suppressed in NB4 cells treated by sodium selenite, as measured by electron microscope, acridine orange staining and western blot. Moreover, selenite combined with autophagy inhibitor contributes to the up-regulation of apoptosis, while the PI3K/Akt signaling pathway is down- regulated. Consistently, when the inhibitor of PI3K was applied, the autophagic level significantly decreased. In summary, sodium selenite increases NB4 cell apoptosis by autophagy inhibition through PI3K/Akt, and the inhibition of autophagy contributes to the up-regulation of apoptosis.

• Molecules and Cells
• /
• 제26권3호
• /
• pp.285-290
• /
• 2008

Estrogen-induced proliferation in estrogen receptor (ER)-positive breast cancer cells is primarily mediated through two distinct intracellular receptors, $ER{\alpha}$ and $ER{\beta}$. Although tumor necrosis factor alpha ($TNF{\alpha}$) and $E2/ER{\alpha}$ are known to exert opposing effects on cell proliferation in MCF-7 cells, the mechanism by which $TNF{\alpha}$ antagonizes $E2/ER{\alpha}$-mediated cell proliferation is not well understood. The present study suggests that reduced cell survival in response to $TNF{\alpha}$ treatment in MCF-7 cells may be associated with the down-regulation of $ER{\alpha}$ protein. The decrease in $ER{\alpha}$ protein level was accompanied by an inhibition of $ER{\alpha}$ gene transcription. Cell viability was decreased synergistically by the combined treatment with $ER{\alpha}$-siRNA and $TNF{\alpha}$. Furthermore, pretreatment of cells with the PI3-kinase (PI3K)/ Akt inhibitor, LY294002, markedly enhanced $TNF{\alpha}$-induced down-regulation of the $ER{\alpha}$ protein, suggesting that the PI3K/Akt pathway might be involved in control of the $ER{\alpha}$ level. Moreover, down-regulation of $ER{\alpha}$ by $TNF{\alpha}$ was not inhibited in cells that were pretreated with the proteasome inhibitors, MG132 and MG152, which suggests that proteasome-dependent proteolysis does not significantly influence $TNF{\alpha}$-induced down-regulation of $ER{\alpha}$ protein. In contrast, the effect of the PI3K/Akt inhibitor on $ER{\alpha}$ was blocked in cells that were treated with LY294002 in the presence of the proteasome inhibitors. Collectively, our findings show that the $TNF{\alpha}$ may partly regulate the growth of MCF-7 breast cancer cells through the down-regulation of $ER{\alpha}$ expression, which is primarily mediated by a PI3K/Akt signaling.