Background The development of persistent endoplasmic reticulum (ER) stress is one of the cornerstones of prostate carcinogenesis; however, the mechanism is missing. Also, alcohol is a physiological ER stress inducer, and the link between alcoholism and progression of prostate cancer (PCa) is well documented but not well characterized. According to the canonical model, the mediator of ER stress, ATF6, is cleaved sequentially in the Golgi by S1P and S2P proteases; thereafter, the genes responsible for unfolded protein response (UPR) undergo transactivation. Methods Cell lines used were non-malignant prostate epithelial RWPE-1 cells, androgen-responsive LNCaP, and 22RV1 cells, as well as androgen-refractory PC-3 cells. We also utilized PCa tissue sections from patients with different Gleason scores and alcohol consumption backgrounds. Several sophisticated approaches were employed, including Structured illumination superresolution microscopy, Proximity ligation assay, Atomic force microscopy, and Nuclear magnetic resonance spectroscopy. Results Herein, we identified the trans-Golgi matrix dimeric protein GCC185 as a Golgi retention partner for both S1P and S2P, and in cells lacking GCC185, these enzymes lose intra-Golgi situation. Progression of prostate cancer (PCa) is associated with overproduction of S1P and S2P but monomerization of GCC185 and its downregulation. Utilizing different ER stress models, including ethanol administration, we found that PCa cells employ an elegant mechanism that auto-activates ER stress by fragmentation of Golgi, translocation of S1P and S2P from Golgi to ER, followed by intra-ER cleavage of ATF6, accelerated UPR, and cell proliferation. The segregation of S1P and S2P from Golgi and activation of ATF6 are positively correlated with androgen receptor signaling, different disease stages, and alcohol consumption. Finally, depletion of ATF6 significantly retarded the growth of xenograft prostate tumors and blocks production of pro-metastatic metabolites. Conclusions We found that progression of PCa associates with translocation of S1P and S2P proteases to the ER and subsequent ATF6 cleavage. This obviates the need for ATF6 transport to the Golgi and enhances UPR and cell proliferation. Thus, we provide the novel mechanistic model of ATF6 activation and ER stress implication in the progression of PCa, suggesting ATF6 is a novel promising target for prostate cancer therapy.

Background The development of persistent endoplasmic reticulum (ER) stress is one of the cornerstones of prostate carcinogenesis; however, the mechanism is missing. Also, alcohol is a physiological ER stress inducer, and the link between alcoholism and progression of prostate cancer (PCa) is well documented but not well characterized. According to the canonical model, the mediator of ER stress, ATF6, is cleaved sequentially in the Golgi by S1P and S2P proteases; thereafter, the genes responsible for unfolded protein response (UPR) undergo transactivation. Methods Cell lines used were non-malignant prostate epithelial RWPE-1 cells, androgen-responsive LNCaP and 22RV1 cells, as wells as androgen-refractory PC-3 cells. We also utilized PCa tissue sections from patients with different Gleason scores and alcohol consumption backgrounds from different. Several sophisticated approaches were employed, including Structured illumination superresolution microscopy, Proximity ligation assay, Atomic force microscopy, and Nuclear magnetic resonance spectroscopy. Results Herein, we identified the trans-Golgi matrix dimeric protein GCC185 as a Golgi retention partner for both S1P and S2P, and in cells lacking GCC185, these enzymes lose intra-Golgi situation. Progression of prostate cancer (PCa) is associated with overproduction of S1P and S2P but monomerization of GCC185 and its downregulation. Utilizing different ER stress models, including ethanol administration, we found that PCa cells employ an elegant mechanism that auto-activates ER stress by fragmentation of Golgi, translocation of S1P and S2P from Golgi to ER, followed by intra-ER cleavage of ATF6, accelerated UPR, and cell proliferation. The segregation of S1P and S2P from Golgi and activation of ATF6 are positively correlated with androgen receptor signaling, different disease stages, and alcohol consumption. Finally, depletion of ATF6 significantly retarded the growth of xenograft prostate tumors and blocks production of pro-metastatic metabolites. Conclusions We found that progression of PCa associates with translocation of S1P and S2P proteases to the ER and subsequent ATF6 cleavage. This obviates the need for ATF6 transport to the Golgi and enhances UPR and cell proliferation. Thus, we provide the novel mechanistic model of ATF6 activation and ER stress implication in the progression of PCa, suggesting ATF6 is a novel promising target for prostate cancer therapy.

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Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary autosomal dominant vascular injury of the brain. Currently, the clinical diagnosis of CADASIL is based on the following criteria: the onset of the condition at a relatively young age (4050 years), recurrent lacunar infarcts, gradual progression of encephalopathy with the development of pseudobulbar syndrome and dementia, various emotional disorders, and autosomal dominant inheritance. Having a family history of relatives with similar symptoms. The diagnosis is verified on the basis of the results of the following studies: neuroimaging, instrumental, morphological, and laboratory. The presence of leukoaraiosis and multiple small bilateral infarctions in such anatomical structures as the basal ganglia and white matter of the cerebral hemispheres, visual tubercles and the pons, and brain stem during MRI diagnostics. Histologically, transmission electron microscopy reveals granular osmiophilic inclusions in the adventitial membrane of the blood vessels of the brain, and on the periphery in the adventitia of the vessels of skeletal muscles and somatic nerves and in vascular biopsies of skin flaps. A mutation in the Notch3 gene determines the clinic of the disease and morphological changes in blood vessels and is detected by a molecular genetic method. The article presents a clinical case, which was a manifestation of this rare hereditary microangiopathy. Clinical case description: A 43-year-old patient was admitted to the Department of Neurology of the Republican Clinical Hospital in Simferopol for ischemic stroke in the basin of the left middle cerebral artery. According to the anamnesis, the patient suffered from migraine without aura from a young age and lacunar strokes; examination revealed a decrease in cognitive function, and MRI showed signs of microangiopathy of cerebral vessels. For final diagnosis, the patient underwent an intravital pathomorphological examination of the biopsy of the musculoskeletal flap; the results obtained made it possible to make a reliable diagnosis of CADASIL. Conclusion: Understanding and knowledge of such a rare pathology as CADASIL is crucial for the rapid recognition of a characteristic clinical picture for further appointment and interpretation of the results of morphological and molecular genetic diagnostics, making it possible to make the correct diagnosis and treatment.

For all tumors, regardless of type and tissue, there are a number of common features. These include high proliferative activity, disturbances in the mechanisms of apoptosis and "invisibility" for the cells of the immune system. At the basis of all these disorders lies a malfunction in the interaction between signaling proteins inside the cell, due to a violation of the expression of genes responsible for their synthesis. The aim of the review is to study the molecular biological mechanisms of carcinogenesis, characteristics and features of tumor cells that affect the development of the disease, progression, drug resistance and clinical results and the possibilities of targeted therapy of oncological diseases. Material and methods. The search for literature sources was carried out using PubMed, CyberLeninka, eLibrary, Google Scholar databases; the search depth was 15 years. Results. Recent works have shown the evolution of views on the classification of tumors from the point of view of the mechanisms of damage to the processes of cellular regulation and histogenesis, as well as the development of the modern theory of carcinogenesis, ideas about the mechanisms of development of tumor diseases and the prospects of modern therapies. Conclusion. The study of molecular biological mechanisms of carcinogenesis, characteristics and features of tumor cells is not only fundamental, but also of applied importance in order to predict the development of the disease, progression, drug resistance, clinical results and the possibilities of targeted therapy.