| 1. |
- Kolosenko, Iryna, et al.
(författare)
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Cell crowding induces interferon regulatory factor 9, which confers resistance to chemotherapeutic drugs
- 2015
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 136:4, s. E51-E61
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Tidskriftsartikel (refereegranskat)abstract
- The mechanism of multicellular drug resistance, defined as the reduced efficacy of chemotherapeutic drugs in solid tumors is incompletely understood. Here we report that colon carcinoma cells cultured as 3D microtissues (spheroids) display dramatic increases in the expression of a subset of type I interferon-(IFN)-stimulated genes (ISGs). A similar gene signature was associated previously with resistance to radiation and chemotherapy, prompting us to examine the underlying biological mechanisms. Analysis of spheroids formed by different tumor cell lines and studies using knock-down of gene expression showed that cell crowding leads to the induction of IFN regulatory factor-9 (IRF9) which together with STAT2 and independently of IFNs, is necessary for ISG upregulation. Increased expression of IRF9 alone was sufficient to induce the ISG subset in monolayer cells and to confer increased resistance to clinically used cytotoxic drugs. Our data reveal a novel mechanism of regulation of a subset of ISGs, leading to drug resistance in solid tumors. What's new? Drug resistance remains a major challenge in the management of cancer patients. Using a 3D model of tumor cells the authors identify cell crowding and the interferon response as important mediators of drug resistance. They demonstrate that interferon regulatory factor 9 (IRF9) and a panel of interferon-stimulated genes are induced by cell crowding in this model. These results link unexpected new molecular mechanisms with the therapy resistance of solid tumors.
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| 2. |
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| 3. |
- Kolosenko, Iryna
(författare)
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Therapeutic response in human cancers : the dual role of STAT signalling
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- STAT proteins were discovered as the mediators of interferon (IFN) signalling in response to viral infections. Later, it has become evident that STATs are activated by many stimuli and that they exert multifaceted effects by regulating gene transcription. Of seven members of the STAT family, my thesis dealt with STAT1, STAT2, and STAT3 and the genes regulated by transcriptional complexes containing them. STAT1 and STAT3 were believed to regulate the opposing functions, the former acting as a tumour suppressor and the latter being an oncogene. Type I IFNs have been used for the treatment of infectious diseases and some types of cancer. In Paper I, we investigated pathways involved in the IFN-induced apoptosis in a myeloma cell line, and what role the STAT1 phosphorylation plays in this model. We used chemical inhibitors of pSTAT1, Akt, mTOR, and cells with a dominant-negative mutant form of STAT1 to evaluate which pathways are essential for the pro-apoptotic effect of IFNα. We have found that pSTAT1 is important, but cooperation with other signalling pathways is necessary to maximize the pro- apoptotic effect of IFNα. In paper II, we used multicellular spheroids (3D culture) as a model to study a gene signature associated with drug resistance. We have found that STAT1, STAT2, and IRF9, as well as IFN- stimulated genes (ISGs), have increased expression in this drug resistance model. Moreover, a similar gene signature is induced in cells cultured for a prolonged time with no trace of IFN detected. The expression of ISGs was not STAT1 dependent but was controlled by STAT2 and IRF9. Overexpression of IRF9 alone was sufficient to drive the transcription of the ISGs and to induce drug resistance in the cells. Therefore, IRF9-induced gene signature can be explored as a marker for therapy response in cancer. In Paper III, we studied the role of the constitutively activated STAT3 in the sensitivity of multiple myeloma cells to the Hsp90 inhibitors treatment. We used a panel of cell lines categorised by different basal levels of the pTyr705STAT3 and of CD45 and found that the sensitivity of myeloma cells to an Hsp90 inhibitor correlated with the presence of pSTAT3. Using samples from multiple myeloma patients, we have demonstrated that it is the pSTAT3+CD45+ cell population that undergoes apoptosis in response to the Hsp90 inhibitor treatment. Thus, pSTAT3/CD45 can be used as a stratification marker for the use of these drugs. In Paper IV, we attempted to develop new inhibitors targeting STAT3. After the screening campaign, we have chosen several inhibitors that preferentially affect the viability in STAT3-dependent cell lines. The inhibitors have different effects on the phosphorylation of STAT3 and STAT1, but regardless of that, all the compounds interfere with the STAT3-driven gene transcription. One of the compounds, KI16, preferentially inhibits the phosphorylation of STAT3 over STAT1. It also docks well to the SH2-domain of STAT3 and has a potential to be developed as a STAT3-targeting drug. Other compounds act through a different mechanism(s), but are also plausible for chemical modifications and development, both as drugs and as molecular probes to identify novel targets important for the full oncogenic function of STAT3. Taken together, our findings demonstrate that the roles of STAT1 and STAT3 in cancer are not strictly determined, but are highly context-dependent. It appears that the IFN/STAT1 signalling can be both pro-apoptotic and pro-survival, whereas the oncogenic JAK/STAT3 axis can be targeted to induce cancer cell death.
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| 4. |
- Pellegrini, Paola, et al.
(författare)
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A drug screening assay on cancer cells chronically adapted to acidosis
- 2018
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Ingår i: Cancer Cell International. - : BMC. - 1475-2867. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Drug screening for the identification of compounds with anticancer activity is commonly performed using cell lines cultured under normal oxygen pressure and physiological pH. However, solid tumors are characterized by a microenvironment with limited access to nutrients, reduced oxygen supply and acidosis. Tumor hypoxia and acidosis have been identified as important drivers of malignant progression and contribute to multicellular resistance to different forms of therapy. Tumor acidosis represents an important mechanism mediating drug resistance thus the identification of drugs active on acid-adapted cells may improve the efficacy of cancer therapy. Methods: Here, we characterized human colon carcinoma cells (HCT116) chronically adapted to grow at pH 6.8 and used them to screen the Prestwick drug library for cytotoxic compounds. Analysis of gene expression profiles in parental and low pH-adapted cells showed several differences relating to cell cycle, metabolism and autophagy. Results: The screen led to the identification of several compounds which were further selected for their preferential cytotoxicity towards acid-adapted cells. Amongst 11 confirmed hits, we primarily focused our investigation on the benzoporphyrin derivative Verteporfin (VP). VP significantly reduced viability in low pH-adapted HCT116 cells as compared to parental HCT116 cells and normal immortalized epithelial cells. The cytotoxic activity of VP was enhanced by light activation and acidic pH culture conditions, likely via increased acid-dependent drug uptake. VP displayed the unique property to cause light-dependent cross-linking of proteins and resulted in accumulation of polyubiquitinated proteins without inducing inhibition of the proteasome. Conclusions: Our study provides an example and a tool to identify anticancer drugs targeting acid-adapted cancer cells.
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| 5. |
- Shah, Kinjal, et al.
(författare)
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PLK1 as a cooperating partner for BCL2-mediated antiapoptotic program in leukemia
- 2023
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Ingår i: Blood Cancer Journal. - 2044-5385. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- The deregulation of BCL2 family proteins plays a crucial role in leukemia development. Therefore, pharmacological inhibition of this family of proteins is becoming a prevalent treatment method. However, due to the emergence of primary and acquired resistance, efficacy is compromised in clinical or preclinical settings. We developed a drug sensitivity prediction model utilizing a deep tabular learning algorithm for the assessment of venetoclax sensitivity in T-cell acute lymphoblastic leukemia (T-ALL) patient samples. Through analysis of predicted venetoclax-sensitive and resistant samples, PLK1 was identified as a cooperating partner for the BCL2-mediated antiapoptotic program. This finding was substantiated by additional data obtained through phosphoproteomics and high-throughput kinase screening. Concurrent treatment using venetoclax with PLK1-specific inhibitors and PLK1 knockdown demonstrated a greater therapeutic effect on T-ALL cell lines, patient-derived xenografts, and engrafted mice compared with using each treatment separately. Mechanistically, the attenuation of PLK1 enhanced BCL2 inhibitor sensitivity through upregulation of BCL2L13 and PMAIP1 expression. Collectively, these findings underscore the dependency of T-ALL on PLK1 and postulate a plausible regulatory mechanism. [Figure not available: see fulltext.]
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