Dual role of Sirtuin 3 in carcinogenesis

Različiti oblici raka jedan od najčešćih uzroka smrtnosti širom svijeta, a s obzirom da mnogi terapeutici vremenom gube djelotvornost, potrebno je razviti nove strategije liječenja. Mnoga istraživanja pokazala da se potencijalne terapije raka mogu bazirati na manipulacijama nad Sirt3, NAD+ ovisne deacetilaze dominantno smještene u mitohondrijima. Sirt3 kontrolira acetilacijski status proteina i tako regulira obranu stanice od stresa, produkciju reaktivnih kisikovih vrsta, metabolizam, ATP sintezu, stanični ciklus, apoptozu i proliferaciju zbog čega se naglašava njegova važna uloga u karcinogenezi. No, ovisno o specifičnom staničnom kontekstu, tj. vrsti raka kao i eksperimentalnim uvjetima, Sirt3 pokazuje ili onkogena ili tumor-supresorska svojstva iz čega proizlazi njegova dualnost. Stoga je cilj ovog rada razjasniti uloge Sirt3 u biologiji raka te objediniti poznate podatke i mehanizme kojima Sirt3 svojim proonkogenim i/ili tumor-supresorskim svojstvima utječe na proliferaciju, metabolizam, metastaziranje, upalu i angiogenezu raka. Na temelju obrađenih podataka za desetak vrsta tumora, može se zaključiti kako su različiti tumor-supresorski ili proonkogeni Sirt3-ovisni mehanizmi prisutni u različitim, ali i unutar istih tipova tumora što dodatno naglašava dualnost. Odnosno kroz aktivaciju i inhibiciju različitih signalnih puteva i/ili transkripcijskih faktora kao i kroz regulaciju razine oksidativnog oštećenja Sirt3 može kontrolirati ishod karcinogeneze pa tako kod raka pluća ne-malih stanica i oralnog raka djeluje kao onkogen, a kod raka pluća malih stanica, raka jetre, žučnih vodova i prostate pokazana je tumor-supresorska uloga. Posebno se zanimljivi rezultati za rak debelog crijeva, jajnika i dojke kod kojih je u različitim ekspreimentima potvrđena i proonkogena i tumor-supresorska uloga unutar istog tipa raka.Cancer is one of the most frequent causes of mortality worldwide, and because of many cancer therapeutics lose their efficiency with time, it is urgent to develop novel curing strategies. Many researches have shown that potential therapies could be based on Sirtuin 3 (Sirt3) manipulation. Sirt3 is NAD+ dependent deacetylase dominantly located in mitochondria that controls protein-acetylation status in cells, regulates cellular stress response, reactive oxygen species (ROS) production, cell metabolism, ATP synthesis, cell cycle, apoptosis and proliferation, thus having a very important role in tumorigenesis. However, depending on the cellular context, type of cancer and experimental conditions Sirt3 can have a dual role – it can act as oncogene and/or tumor supressor. Therefore, aim of this paper is to elucidate roles of Sirt3 in cancer biology and to assemble known information and mechanisms on how Sirt3, with its oncogene or tumor supressor properties, affects cancer proliferation, metabolism, metastasis, inflamation and angiogenesis. Based on processed data for several cancer types, it could be concluded that different oncogene or tumor supressor Sirt3-depended mechanisms are present in the different, but also within the same types of cancer, which further emphasizes duality of Sirt3. Thus, through activation or inhibiton of various signling pathways and/or transcriptional factors along with oxidative damage regulation, Sirt3 controls outcome of carcinogenesis. For inastance, Sirt3 acts as oncogen in non-small cell lung cancer and oral cancer, whereas in small-cell lung cancer, hepatocelullar carcinoma, cholangiocarcinoma and prostate cancer as tumor suppressor. Results for colorectal, ovarian and breast cancer are especially interesting because researches have sh

Dual role of Sirtuin 3 in carcinogenesis

Različiti oblici raka jedan od najčešćih uzroka smrtnosti širom svijeta, a s obzirom da mnogi terapeutici vremenom gube djelotvornost, potrebno je razviti nove strategije liječenja. Mnoga istraživanja pokazala da se potencijalne terapije raka mogu bazirati na manipulacijama nad Sirt3, NAD+ ovisne deacetilaze dominantno smještene u mitohondrijima. Sirt3 kontrolira acetilacijski status proteina i tako regulira obranu stanice od stresa, produkciju reaktivnih kisikovih vrsta, metabolizam, ATP sintezu, stanični ciklus, apoptozu i proliferaciju zbog čega se naglašava njegova važna uloga u karcinogenezi. No, ovisno o specifičnom staničnom kontekstu, tj. vrsti raka kao i eksperimentalnim uvjetima, Sirt3 pokazuje ili onkogena ili tumor-supresorska svojstva iz čega proizlazi njegova dualnost. Stoga je cilj ovog rada razjasniti uloge Sirt3 u biologiji raka te objediniti poznate podatke i mehanizme kojima Sirt3 svojim proonkogenim i/ili tumor-supresorskim svojstvima utječe na proliferaciju, metabolizam, metastaziranje, upalu i angiogenezu raka. Na temelju obrađenih podataka za desetak vrsta tumora, može se zaključiti kako su različiti tumor-supresorski ili proonkogeni Sirt3-ovisni mehanizmi prisutni u različitim, ali i unutar istih tipova tumora što dodatno naglašava dualnost. Odnosno kroz aktivaciju i inhibiciju različitih signalnih puteva i/ili transkripcijskih faktora kao i kroz regulaciju razine oksidativnog oštećenja Sirt3 može kontrolirati ishod karcinogeneze pa tako kod raka pluća ne-malih stanica i oralnog raka djeluje kao onkogen, a kod raka pluća malih stanica, raka jetre, žučnih vodova i prostate pokazana je tumor-supresorska uloga. Posebno se zanimljivi rezultati za rak debelog crijeva, jajnika i dojke kod kojih je u različitim ekspreimentima potvrđena i proonkogena i tumor-supresorska uloga unutar istog tipa raka.Cancer is one of the most frequent causes of mortality worldwide, and because of many cancer therapeutics lose their efficiency with time, it is urgent to develop novel curing strategies. Many researches have shown that potential therapies could be based on Sirtuin 3 (Sirt3) manipulation. Sirt3 is NAD+ dependent deacetylase dominantly located in mitochondria that controls protein-acetylation status in cells, regulates cellular stress response, reactive oxygen species (ROS) production, cell metabolism, ATP synthesis, cell cycle, apoptosis and proliferation, thus having a very important role in tumorigenesis. However, depending on the cellular context, type of cancer and experimental conditions Sirt3 can have a dual role – it can act as oncogene and/or tumor supressor. Therefore, aim of this paper is to elucidate roles of Sirt3 in cancer biology and to assemble known information and mechanisms on how Sirt3, with its oncogene or tumor supressor properties, affects cancer proliferation, metabolism, metastasis, inflamation and angiogenesis. Based on processed data for several cancer types, it could be concluded that different oncogene or tumor supressor Sirt3-depended mechanisms are present in the different, but also within the same types of cancer, which further emphasizes duality of Sirt3. Thus, through activation or inhibiton of various signling pathways and/or transcriptional factors along with oxidative damage regulation, Sirt3 controls outcome of carcinogenesis. For inastance, Sirt3 acts as oncogen in non-small cell lung cancer and oral cancer, whereas in small-cell lung cancer, hepatocelullar carcinoma, cholangiocarcinoma and prostate cancer as tumor suppressor. Results for colorectal, ovarian and breast cancer are especially interesting because researches have sh

Dual role of Sirtuin 3 in carcinogenesis

Različiti oblici raka jedan od najčešćih uzroka smrtnosti širom svijeta, a s obzirom da mnogi terapeutici vremenom gube djelotvornost, potrebno je razviti nove strategije liječenja. Mnoga istraživanja pokazala da se potencijalne terapije raka mogu bazirati na manipulacijama nad Sirt3, NAD+ ovisne deacetilaze dominantno smještene u mitohondrijima. Sirt3 kontrolira acetilacijski status proteina i tako regulira obranu stanice od stresa, produkciju reaktivnih kisikovih vrsta, metabolizam, ATP sintezu, stanični ciklus, apoptozu i proliferaciju zbog čega se naglašava njegova važna uloga u karcinogenezi. No, ovisno o specifičnom staničnom kontekstu, tj. vrsti raka kao i eksperimentalnim uvjetima, Sirt3 pokazuje ili onkogena ili tumor-supresorska svojstva iz čega proizlazi njegova dualnost. Stoga je cilj ovog rada razjasniti uloge Sirt3 u biologiji raka te objediniti poznate podatke i mehanizme kojima Sirt3 svojim proonkogenim i/ili tumor-supresorskim svojstvima utječe na proliferaciju, metabolizam, metastaziranje, upalu i angiogenezu raka. Na temelju obrađenih podataka za desetak vrsta tumora, može se zaključiti kako su različiti tumor-supresorski ili proonkogeni Sirt3-ovisni mehanizmi prisutni u različitim, ali i unutar istih tipova tumora što dodatno naglašava dualnost. Odnosno kroz aktivaciju i inhibiciju različitih signalnih puteva i/ili transkripcijskih faktora kao i kroz regulaciju razine oksidativnog oštećenja Sirt3 može kontrolirati ishod karcinogeneze pa tako kod raka pluća ne-malih stanica i oralnog raka djeluje kao onkogen, a kod raka pluća malih stanica, raka jetre, žučnih vodova i prostate pokazana je tumor-supresorska uloga. Posebno se zanimljivi rezultati za rak debelog crijeva, jajnika i dojke kod kojih je u različitim ekspreimentima potvrđena i proonkogena i tumor-supresorska uloga unutar istog tipa raka.Cancer is one of the most frequent causes of mortality worldwide, and because of many cancer therapeutics lose their efficiency with time, it is urgent to develop novel curing strategies. Many researches have shown that potential therapies could be based on Sirtuin 3 (Sirt3) manipulation. Sirt3 is NAD+ dependent deacetylase dominantly located in mitochondria that controls protein-acetylation status in cells, regulates cellular stress response, reactive oxygen species (ROS) production, cell metabolism, ATP synthesis, cell cycle, apoptosis and proliferation, thus having a very important role in tumorigenesis. However, depending on the cellular context, type of cancer and experimental conditions Sirt3 can have a dual role – it can act as oncogene and/or tumor supressor. Therefore, aim of this paper is to elucidate roles of Sirt3 in cancer biology and to assemble known information and mechanisms on how Sirt3, with its oncogene or tumor supressor properties, affects cancer proliferation, metabolism, metastasis, inflamation and angiogenesis. Based on processed data for several cancer types, it could be concluded that different oncogene or tumor supressor Sirt3-depended mechanisms are present in the different, but also within the same types of cancer, which further emphasizes duality of Sirt3. Thus, through activation or inhibiton of various signling pathways and/or transcriptional factors along with oxidative damage regulation, Sirt3 controls outcome of carcinogenesis. For inastance, Sirt3 acts as oncogen in non-small cell lung cancer and oral cancer, whereas in small-cell lung cancer, hepatocelullar carcinoma, cholangiocarcinoma and prostate cancer as tumor suppressor. Results for colorectal, ovarian and breast cancer are especially interesting because researches have sh

Sirt3 Exerts Its Tumor-Suppressive Role by Increasing p53 and Attenuating Response to Estrogen in MCF-7 Cells

Estrogen (E2) is a major risk factor for the initiation and progression of malignancy in estrogen receptor (ER) positive breast cancers, whereas sirtuin 3 (Sirt3), a major mitochondrial NAD+-dependent deacetylase, has the inhibitory effect on the tumorigenic properties of ER positive MCF-7 breast cancer cells. Since it is unclear if this effect is mediated through the estrogen receptor alpha (ERα) signaling pathway, in this study, we aimed to determine if the tumor-suppressive function of Sirt3 in MCF-7 cells interferes with their response to E2. Although we found that Sirt3 improves the antioxidative response and mitochondrial fitness of the MCF-7 cells, it also increases DNA damage along with p53, AIF, and ERα expression. Moreover, Sirt3 desensitizes cells to the proliferative effect of E2, affects p53 by disruption of the ERα–p53 interaction, and decreases proliferation, colony formation, and migration of the cells. Our observations indicate that these tumor-suppressive effects of Sirt3 could be reversed by E2 treatment only to a limited extent which is not sufficient to recover the tumorigenic properties of the MCF-7 cells. This study provides new and interesting insights with respect to the functional role of Sirt3 in the E2-dependent breast cancers

Enhancing natural killer cells proliferation and cytotoxicity using imidazole-based lipid nanoparticles encapsulating interleukin-2 mRNA

International audiencemRNA applications have undergone unprecedented applications-from vaccination to cell therapy. Natural killer (NK) cells are recognized to have a significant potential in immunotherapy. NK-based cell therapy has drawn attention as allogenic graft with a minimal graft-versus-host risk leading to easier off-the-shelf production. NK cells can be engineered with either viral vectors or electroporation, involving high costs, risks, and toxicity, emphasizing the need for alternative way as mRNA technology. We successfully developed, screened, and optimized novel lipid-based platforms based on imidazole lipids. Formulations are produced by microfluidic mixing and exhibit a size of approximately 100 nm with a polydispersity index of less than 0.2. They are able to transfect NK-92 cells, KHYG-1 cells, and primary NK cells with high efficiency without cytotoxicity, while Lipofectamine Messenger Max and D-Lin-MC3 lipid nanoparticle-based formulations do not. Moreover, the translation of non-modified mRNA was higher and more stable in time compared with a modified one. Remarkably, the delivery of therapeutically relevant interleukin 2 mRNA resulted in extended viability together with preserved activation markers and cytotoxic ability of both NK cell lines and primary NK cells. Altogether, our platforms feature all prerequisites needed for the successful deployment of NK-based therapeutic strategies