22 research outputs found
GSTA4 governs melanoma cell resistance to anti tumor immunity
No full text富山大学博士（薬科学）Article富山大学・富医薬博甲第422号・Ucche Sisca・2023/03/23
公表論文
1.Mojic M, Shitaoka K, Ohshima C, Ucche S, Lyu F, Hamana H, Tahara H, Kishi H, Hayakawa Y.
NKG2D defines tumor-reacting effector CD8+ T cells within tumor microenvironment.
Cancer Sci. 2021 Sep;112(9):3484-3490. doi: 10.1111/cas.15050. Epub 2021 Jul 28. PMID: 34187084; PMCID: PMC8409295.
2.Ucche S, Yokoyama S, Mojic M, Oki K, Ohshima C, Tsuihiji H, Takasaki I, Tahara H, Hayakawa Y.
GSTA4 Governs Melanoma Immune Resistance and Metastasis.
Mol Cancer Res. 2023 Jan 3;21(1):76-85. doi: 10.1158/1541-7786.MCR-22-0369. PMID: 36162957
Immunological Aspects of Cancer Cell Metabolism
No full textCancer cells adeptly manipulate their metabolic processes to evade immune detection, a phenomenon intensifying the complexity of cancer progression and therapy. This review delves into the critical role of cancer cell metabolism in the immune-editing landscape, highlighting how metabolic reprogramming facilitates tumor cells to thrive despite immune surveillance pressures. We explore the dynamic interactions within the tumor microenvironment (TME), where cancer cells not only accelerate their glucose and amino acid metabolism but also induce an immunosuppressive state that hampers effective immune response. Recent findings underscore the metabolic competition between tumor and immune cells, particularly focusing on how this interaction influences the efficacy of emerging immunotherapies. By integrating cutting-edge research on the metabolic pathways of cancer cells, such as the Warburg effect and glutamine addiction, we shed light on potential therapeutic targets. The review proposes that disrupting these metabolic pathways could enhance the response to immunotherapy, offering a dual-pronged strategy to combat tumor growth and immune evasion
Massoia Lactone: Production Technologies, Multisectoral Applications, and Toxicological Evaluation
No full textMassoia lactone is a delta-lactone that occurs naturally in the bark oil of Cryptocarya massoy, recognized for its sweet, coconut-like scent and extensive industrial applications. This area is increasingly relevant in food, pharmaceuticals, agriculture, and veterinary applications. C-10 Massoia lactone has been designated as Generally Recognized As Safe (GRAS) by the Flavor and Extract Manufacturers Association (FEMA); however, its regulatory review remains in progress. This narrative review examines the structural features, production methods, applications, and toxicological profile. A systematic literature search was performed using Scopus, PubMed, and Google Scholar with the terms “Massoia lactone,” “Massoilactone,” and “masoilakton,” yielding 21 eligible articles. The studies reviewed outline different production methods, such as plant extraction, fungal fermentation, and chemical synthesis, along with the physicochemical properties and applications of C-10, C-12, and C-14 homologs. Massoia lactone demonstrates potential applications in food preservation, oral biofilm management, and antifungal treatment in aquaculture, exhibiting minimal safety risks when used under regulated conditions. This review synthesizes insights from natural product chemistry, pharmacognosy, biotechnology, and toxicology to advocate for sustainable utilization. Further research is necessary to elucidate its mechanisms of action and assess long-term safety
Massoia Lactone: Production Technologies, Multisectoral Applications, and Toxicological Evaluation
No full textMassoia lactone is a delta-lactone that occurs naturally in the bark oil of Cryptocarya massoy, recognized for its sweet, coconut-like scent and extensive industrial applications. This area is increasingly relevant in food, pharmaceuticals, agriculture, and veterinary applications. C-10 Massoia lactone has been designated as Generally Recognized As Safe (GRAS) by the Flavor and Extract Manufacturers Association (FEMA); however, its regulatory review remains in progress. This narrative review examines the structural features, production methods, applications, and toxicological profile. A systematic literature search was performed using Scopus, PubMed, and Google Scholar with the terms “Massoia lactone,” “Massoilactone,” and “masoilakton,” yielding 21 eligible articles. The studies reviewed outline different production methods, such as plant extraction, fungal fermentation, and chemical synthesis, along with the physicochemical properties and applications of C-10, C-12, and C-14 homologs. Massoia lactone demonstrates potential applications in food preservation, oral biofilm management, and antifungal treatment in aquaculture, exhibiting minimal safety risks when used under regulated conditions. This review synthesizes insights from natural product chemistry, pharmacognosy, biotechnology, and toxicology to advocate for sustainable utilization. Further research is necessary to elucidate its mechanisms of action and assess long-term safety
Control of IFN-γ Responsiveness and Metastatic Potential in Melanoma by GSTA4
No full textBackground: Interferon-gamma (IFNγ) is a crucial eff ector molecule of antitumor immunity. This cytokine promotes the excessive production of reactive oxygen species (ROS) in tumor cells, which leads to DNA damage and senescence [1]. Recently it has been discovered that IFNγ can also trigger cancer cell ferroptosis by fostering lipid peroxidation [2]. Cancers often evade antitumor immunity by losing their responsiveness to IFNγ. Consequently, IFNγ becomes a critical player in the immunoediting process, selecting tumor cells with immunoevasive properties [3]. Defects in responsiveness to IFNγ in cancer cells significantly contribute to the limited success of cancer immunotherapy in clinics [4], emphasizing the importance of understanding the mechanism behind the IFNγ-mediated immunoeding process. To
address this issue, we investigated how tumor cells escape IFNγ-dependent immune response through immunoediting by analyzing originally established immune-escape variants of melanoma cells. Material and Methods: We used a previously established in vivo model in which antitumor immunity was IFNγ dependent [5]. Mouse B16 melanoma cells expressing ovalbumin as a tumor-specific antigen (B16OVA) were subcutaneously inoculated in OVA-immunized B6 mice. In this model, tumor growth suppression by host IFN-γ lasts for a limited time, after which all tumors progress. Next, we established cancer cell lines with different in vivo immunological experiences. Tumor cells were isolated from same-sized tumors from wild-type (WT) untreated mice (established cell lines were named "NIMM"), from WT OVAimmunized
mice after the cessation of immune control of tumor growth (established cell lines were named "IMM"), or
from IFNγ knockout (IFNγ KO) OVA-immunized mice (established cell lines were named "GKO-IMM"). IMM, NIMM, and GKO-IMM cells were re-challenged in OVA-immunized mice to test their ability to provoke antitumor immunity. Instead of immunization with OVA antigen, in some experiments, the anti-PD-1 antibody was administered intraperitoneally to initiate tumor-specific immunity in vivo. To examine changes in phenotype resulting from the IFNγ immunoediting process, total RNA was extracted from parental B16OVA cells and immune-escaped IMM cells. Gene expression was analyzed using a GeneChip system with GeneChip Mouse Gene 2.0 ST Array. mRNA and protein expression of selected genes was quantitatively determined by real-time PCR and western blotting, respectively. GSTA4 overexpression or knockdown was performed to determine its functional role in the immunoevasive phenotype of IMM cells. Cell sensitivity to IFNγ and 4–hydroxynonenal (4–HNE), a lipid peroxidation product, was estimated by WST–8 cell viability assay. CellROX Deep Red reagent was used to detect IFNγ-induced intracellular ROS accumulation. Transwell invasion assay was used
to assess melanoma cells' in vitro metastatic potential. In the in vivo experimental lung metastasis model, cells were injected into the tail vein and metastasized tumor colonies on the surface of the lungs were counted. The correlation of GSTA4 expression in human melanoma patients with tumor-free survival rates, and response to anti–PD1 treatment in correlation with GSTA4 expression and survival rates were obtained from publicly available databases. Results: Upon re-challenging into OVA-immunized mice, IMM cells showed unrestrained progression, while the growth of NIMM and GKO-IMM tumors was suppressed. In addition, only IMM cells specifically lost OVA antigen expression, indicating that these cells gained the ability to evade the OVA-specific antitumor immune response. In line with in vivo data, IFNγ treatment in vitro reduced the viability of parental B16OVA, NIMM, and GKO-IMM cells, while the viability of IMM cells was intact. Interestingly, IFNγ upregulated the expression of MHC class I (H-2Kd) and PD-L1in IMM cells,
suggesting that these cells did not have the defect in IFNγ signaling. We found that the lack of IMM cell responsiveness to the IFNγ-induced cytostatic effect was due to the acquisition of resistance to the IFNγ-induced oxidative stress response. Gene expression analysis using DNA microarray revealed that the most upregulated gene in immunoevasive IMM cells was glutathione-S-transferase-4 (GSTA4). GSTA4 is a member of a family of detoxification enzymes that play an essential protective role in cellular oxidative stress responses [6]. GSTA4 overexpression in parental B16OVA cells reduced ROS production and increased their resistance to the IFNγ-induced cytostatic effect in vitro. Consequently, the growth of B16OVA cells overexpressing GSTA4 was more aggressive in OVA-immunized mice than that of parental
B16OVA cells. In parallel, the knockdown of GSTA4 in IMM cells led to increased intracellular ROS levels and decreased viability upon in vitro IFNγ treatment. IMM tumors were resistant to anti-PD1 treatment in vivo, and the knockdown of GSTA4 reinvigorated their responsiveness. In addition to the role in acquired resistance to IFNγ, we found that the upregulation of GSTA4 was also responsible for the higher metastatic potential of IMM tumors. Next, we confirmed the results from the mouse model in human melanoma. GSTA4 expression levels in Malme3M, UACC 62, and MeWo melanoma cell lines inversely correlated with their sensitivity to in vitro IFNγ treatment. Database analysis revealed a significant correlation between the expression of GSTA4 and the metastasis-free survival rate of human melanoma
patients. Melanoma patients with low GSTA4 expression were better responders and showed a better progression-free survival rate to anti-PD1 therapy, further supporting the clinical relevance of our findings. Conclusion: In this study, we uncovered a new mechanism through which cancer cells evade immune surveillance and enhance their ability to metastasize by developing resistance to oxidative stress responses through GSTA4 upregulation. Our results suggest that targeting the oxidative stress response in cancer cells emerges as a promising therapeutic strategy to overcome immune resistance and regulate the progression of metastasis [7].Proceedings book of The Sixth Congress of The Serbian Association for Cancer Research with international participation: From Collaboration to Innovation in Cancer Research; 2023 Oct 2-4; Belgrade, Serbia. Belgrade, Serbia: Serbian Associaton for Cancer Research; 2023. p. 50-1. (Oncology Insights; No. 1)
GSTA4 upregulation promotes melanoma immune evasion and metastasis
No full textIFNγ је кључни цитокин антитуморског имунског одговора. У ћелијама канцера, IFNγ стимулише производњу реактивних врста кисеоника. Настало стање
оксидативног стреса доводи до оштећења ДНК и, последично, до сенесценције
или до фероптозе, ћелијске смрти посредоване пероксидацијом липида. Неадекватан одговор на IFNγ је честа одлика канцера са способних да „побегну“
антитуморском имунском одговору. Уједно, овај дефект у одговору на IFNγ се
сматра значајним чиниоцем ограниченог успеха имунотерапије код пацијанта
са канцером.
У овој студији, истражили смо како ћелије тумора избегавају антитуморски
имунски одговор посредован цитокином IFNγ. Успоставили смо ћелијске линије меланома које су „побегле“ антитуморском имунском одговору и анализирали смо промене у њиховом фенотипу. Открили смо да су ћелије меланома
које су избегле имунски одговор развиле резистенцију на оксидативни стрес
индукован IFNγ. Кључни играч у овом процесу је глутатион-С-трансфераза
(енг.GSTA4), члан породице ензима за детоксикацију који имају важну улогу у
ћелијском одговору на оксидативни стрес. Осим тога, ћелије меланома које су
избегле имунски одговор су стекле већи метастатски потенцијал in vivo, такође
зависан од повећаног нивоа експресије GSTA4. Код пацијената са меланомом
утврђено је да нижи ниво експресије GSTA4 корелира са бољом стопом преживљавања без метастаза. Такође, пацијенти са меланомом код којих је нижа
GSTA4 екпресија боље реагују на анти-PD1 терапију и имају су бољу стопу преживљавања без прогресије тумора.
Наши резултати расветљавају нови механизам помоћу којег ћелије канцера избегавају имунолошки надзор и повећавају свој метастатски потенцијал, развијањем резистенције на оксидативни стрес услед повећане експресије GSTA4. Стога,
таргетирање молекула у одговору канцера на оксидативни стрес представља обећавајући терапеутски приступ за превазилажење резистенције на антитуморски
имунски одговор и регулисање метастазирања.IFNγ is a crucial cytokine in antitumor immunity. In cancer cells, IFNγ promotes excessive
production of the reactive oxygen species. Oxidative stress leads to DNA damage
and, consequently, triggers cellular senescence or ferroptosis, a type of cell death associated
with increased lipid peroxidation. The IFNγ response defect is commonly observed in
cancers that exhibit immunoevasive properties. This defect is considered a significant factor
contributing to the limited success of cancer immunotherapy in patients with cancer.
In this study, we explored how tumor cells evade the IFNγ-dependent immune response.
We established immune-escape variants of melanoma cells and analyzed changes in their
phenotype. We found that the immune-escape melanoma variants gained resistance to
the IFNγ-induced oxidative stress response. The critical molecule in this process was glutathione-
S-transferase-4 (GSTA4), a member of a family of detoxification enzymes that
play an important role in cellular oxidative stress responses. In addition to the resistance
to IFNγ-mediated antitumor immunity, the immune-escape melanoma variants acquired
higher metastatic ability in vivo by a GSTA4-dependent mechanism. Melanoma patients
with lower expression of GSTA4 had better prognosis in terms of metastasis-free survival
rate. Additionally, melanoma patients with low GSTA4 expression were better responders
to anti-PD1 therapy and showed a better progression-free survival rate.
Our results reveal a novel mechanism by which cancer cells escape from immune
surveillance and increase metastatic potential by developing resistance to oxidative
stress responses through GSTA4 upregulation. Therefore, targeting the oxidative stress
response in cancer cells presents a promising therapeutic approach for overcoming immune
resistance and regulating metastatic progression.Arsenijević N, editor. Abstract Book: The second Serbian Molecular Medicine Congress; 2023 Oct 6-8; Foča, Bosnia and Herzegovina. Kragujevac: Serbian Society for Immunology, Molecular Oncology and Regenerative Medicine; 2023. p. 53-5
Business Development Strategy of Nii Kutchen Bakery Bengkalis Using Business Model Canvas and SWOT Analysis
No full textThis study aims to design a strategy for developing a Bakery business using the Business Model Canvas and SWOT Analysis approach at Nii Kutchen Bakery Bengkalis. The type of research used by the author is descriptive qualitative with the aim of designing new strategies that are used to maintain business and develop businesses that are increasingly competitive. Data collection techniques in this study were interviews, observation and documentation. The object of this research is Nii Kutchen Bakery Bengkalis. The results of the study show that the results of the Business Model Canvas at Nii Kutchen Bakery Bengkalis indicate the need for a new strategy change because there are still many segments that cannot compete with competitors. So it can be concluded that it is necessary to design a new strategy through SWOT Analysis on each element of the Business Model Canvas to be implemented by Nii Kutchen Bakery Bengkalis in the future
Calorie Restriction Impairs Anti-Tumor Immune Responses in an Immunogenic Preclinical Cancer Model
No full text(1) Background: Although the important role of dietary energy intake in regulating both cancer progression and host immunity has been widely recognized, it remains unclear whether dietary calorie restriction (CR) has any impact on anti-tumor immune responses. (2) Methods: Using an immunogenic B16 melanoma cell expressing ovalbumin (B16-OVA), we examined the effect of the CR diet on B16-OVA tumor growth and host immune responses. To further test whether the CR diet affects the efficacy of cancer immunotherapy, we examined the effect of CR against anti-PD-1 monoclonal antibody (anti-PD-1 Ab) treatment. (3) Results: The CR diet significantly slowed down the tumor growth of B16-OVA without affecting both CD4+ and CD8+ T cell infiltration into the tumor. Although in vivo depletion of CD8+ T cells facilitated B16-OVA tumor growth in the control diet group, there was no significant change in the tumor growth in the CR diet group with or without CD8+ T cell-depletion. Anti-PD-1 Ab treatment lost its efficacy to suppress tumor growth along with the activation and metabolic shift of CD8+ T cells under CR condition. (4) Conclusions: Our present results suggest that a physical condition restricted in energy intake in cancer patients may impair CD8+ T cell immune surveillance and the efficacy of immunotherapy
Perbandingan Return dan Risiko Investasi pada Saham Syariah dan Emas
No full textAbstrak – Sebelum memutuskan untuk berinvestasi, investor perlu melakukan analisa terhadap return dan risiko dari investasi yang akan dilakukan. Oleh karena itu, penelitian ini bertujuan untuk membandingkan return dan risiko investasi pada saham syariah dan emas. Periode penelitian dari Januari 2004 sampai Desember 2013. Data yang digunakan merupakan data historis harga saham ANTM, UNTR, UNVR, dan harga emas. Analisis data menggunakan uji-t (independent sample t-test). Hasil dari penelitian ini membuktikan bahwa berinvestasi dalam emas lebih menguntungkan dibandingkan dengan berinvestsasi dalam saham syariah karena return emas lebih tinggi dari saham syariah dan risiko emas lebih rendah dari saham syariah. Abstract – Before deciding to invest, investors should conduct an analysis of the returns and risks of the investment that he will make. Therefore, this study is to determine the differences of return and risk between real gold investment on sharia stocks during the period January 2004 to December 2013. The Author used stock prices historical data of ANTM, UNTR, UNVR, and the price of real gold in doing this study. T-test (independent sample t-test) also been used as data analysis. The results of this study proved that investing in real gold instrument is considered more profitable than investing in sharia stocks, because the real gold return is higher than the sharia stocks return and the real gold risk is lower than the sharia stocks risk. Keywords – Investment, real gold, sharia stock
