This review discusses the role of the multifunctional DNA/RNA-binding protein YB-1 in inflammation. YB-1 performs multiple functions in the cell depending on its location: it acts as transcriptional factor for many genes in the nucleus, regulates translation and stability of mRNA in the cytoplasm, and becomes a paracrine factor when secreted from the cells. The review presents the data on the YB-1-mediated regulation of inflammation-associated genes, as well as results of studies on the YB-1 role in animal model of various inflammatory diseases, such as glomerulonephritis, tubulointerstitial fibrosis, and bacterial sepsis, and on the YB-1 expression in different human diseases associated with inflammatory processes in kidney, liver, and endometrium. The last section of the review presents several approaches to the regulation of YB-1 with small molecules in the treatment of inflammatory diseases.

The aims of this study were to develop co-delivery systems of paclitaxel (PTX) and etoposide prodrug (4´-O-benzyloxycarbonyl-etoposide, ETP-cbz) based on non-cross-linked human serum albumin (HSA) and poly(lactide-co-glycolide) nanoparticles and to evaluate the synergistic potential of these drugs in vitro. The nanoformulations were prepared by the high-pressure homogenization technique and characterized using DLS, TEM, SEM, AFM, HPLC, CZE, in-vitro release, and cytotoxicity in human and murine glioma cells. All nanoparticles had 90-150 nm in size and negative ζ-potentials. The Neuro2A cells were the most sensitive to both HSA- and PLGA-based co-delivery systems (IC₅₀ 0.024 µM and 0.053 µM, respectively). The drugs’ synergistic effect (combination index < 0.9) was observed in the GL261 cells for both types of the co-delivery formulations and in the Neuro2A cells for the HSA-based system. These nanodelivery systems may be useful to improve combination chemotherapy for brain tumor treatment. To our knowledge, this is the first report describing the non-cross-linked HSA-based co-delivery nanosuspension which was prepared using nab™ technology.

Soft tissue sarcomas (STS) are heterogeneous cancers with more than 100 histological subtypes, different in molecular alterations, which make its personalized therapy very complex. Gold standard of chemotherapy for advanced STS includes combinations of Doxorubicin and Ifosfamide or Gemcitabine and Docetaxel. Chemotherapy is efficient for less than 50% of patients and it is followed by a fast development of drug resistance. Our study was directed to the search of genetic alterations in cancer cells associated with chemoresistance of undifferentiated pleomorphic and synovial sarcomas to the abovementioned genotoxic drugs. We analyzed chemoresistance of cancer cells in vitro using primary STS cultures and performed genetic analysis for the components of apoptotic signaling. In 27% of tumors, we revealed alterations in TP53, ATM, PIK3CB, PIK3R1, NTRK1, and CSF2RB. Cells from STS specimens with found genetic alterations were resistant to Dox, excluding the only one case when TP53 mutation resulted in the substitution Leu344Arg associated with partial oligomerization loss and did not cause total loss of TP53 function. Significant association between alterations in the components of apoptosis signaling and chemoresistance to Dox was found. Our data are important to elaborate further the therapeutic strategy for STS patients with alterations in apoptotic signaling.

Chemotherapy of soft tissue sarcomas (STS) is restricted by low chemosensitivity and multiple drug resistance (MDR). The purpose of our study was the analysis of MDR mechanism in different types of STS. We assessed the expression of ABC-transporters, MVP, YB-1, and analyzed their correlation with chemosensitivity of cancer cells. STS specimens were obtained from 70 patients without metastatic disease (2018–2020). Expression level of MDR-associated genes was estimated by qRT-PCR and cytofluorimetry. Mutations in ABC-transporter genes were captured by exome sequencing. Chemosensitivity (SI) of STS to doxorubicin (Dox), ifosfamide (Ifo), gemcitabine (Gem), and docetaxel (Doc) was analyzed in vitro. We found strong correlation in ABCB1, ABCC1, and ABCG2 expression. We demonstrated strong negative correlations in ABCB1 and ABCG2 expression with SI (Doc) and SI (Doc + Gem), and positive correlation of MVP expression with SI (Doc) and SI (Doc + Gem) in undifferentiated pleomorphic sarcoma. Pgp expression was shown in 5 out of 44 STS samples with prevalence of synovial sarcoma relapses and it is strongly correlated with SI (Gem). Mutations in MDR-associated genes were rarely found. Overall, STS demonstrated high heterogeneity in chemosensitivity that makes reasonable in vitro chemosensitivity testing to improve personalized STS therapy, and classic ABC-transporters are not obviously involved in MDR appearance.

Y-box binding protein 1 (YB-1) is a member of the large protein family with an evolutionarily ancient coldshock domain. It is involved in the regulation of some global traits of malignancy and functions both in the cell nucleus and cytoplasm. We investigated the content of YB-1 mRNA and proportion of cells with YB-1 nuclear localization in breast cancer (BC) tumors taken at mastectomy. We showed that an increased level of YB-1 mRNA in samples correlated with tumor aggressiveness and increased expression of multidrug resistance (MDR) genes. Over-expression of several MDR genes was found in the samples with high YB-1 mRNA content and with YB-1 cytoplasmic localization. This suggests that YB-1 regulates expression of some MDR genes at the level of cytoplasm. The nuclear YB-1 localization also correlated with BC aggressiveness; however, these interconnections were less prominent in comparison with those between a high YB-1 mRNA content and the mentioned tumor characteristics. Our results show that neo-adjuvant chemotherapy induces translocation of YB-1 from the cytoplasm to the cell nucleus in mammary tumors. In the experiments with cell cultures we showed that chemotherapeutic drugs stimulated YB-1 nuclear translocation, as well as MDR genes expression and cell multidrug resistance. We suppose that YB-1 nuclear translocation determines adaptation of tumor cell populations to the environmental impact, while a high YB-1 mRNA content is an intrinsic feature that contributes to the control of the global traits of malignancy. A combination YB-1 mRNA content and its intracellular localization may serve as a test for BC prognosis.