An Arthropod Hormone, Ecdysterone, Inhibits the Growth of Breast Cancer Cells via Different Mechanisms.

Ecdysterone (Ecdy) is a hormone found in arthropods, which regulates their development. It is also synthesized by a number of plants to combat insect pests. It provides a number of beneficial pharmacological effects including the anabolic and adaptogenic ones. Ecdysterone is widely marketed as food supplement to enhance the physical performance of athletes. In addition to the estrogen receptor beta (ERbeta)-dependent anabolic effect of Ecdy in muscles, the molecular mechanisms of the plethora of other Ecdy-induced pharmacological effects remain unknown. The aim of this study was to investigate the pharmacological effect of ecdysterone on human breast cancer cell lines of different molecular subtypes. Surprisingly, in contrast to the anabolic effect on muscle tissues, we have revealed a tumor suppressive effect of Ecdy on a panel of breast cancer cell lines studied. Using the SeaHorse-based energy profiling, we have demonstrated that Ecdy dampened glycolysis and respiration, as well as greatly reduced the metabolic potential of triple negative breast cancer cell lines. Furthermore, we have revealed that Ecdy strongly induced autophagy. As part of the combined treatment, based on the Combination Index (CI) and Dose Reduction Index (DRI), Ecdy synergized with doxorubicin to induce cell death in several breast cancer cell lines. In contrast, Ecdy had only minor effect on non-transformed human fibroblasts. Collectively, our results indicate that ecdysterone can be considered as a new potential adjuvant for genotoxic therapy in treatment of breast cancer patients.

The Role of ERBB2/HER2 Tyrosine Kinase Receptor in the Regulation of Cell Death.

HER2 (Human Epidermal Growth Factor Receptor 2), also known as ERBB2, CD340, and Neu protooncogene, is a member of the epidermal growth factor receptor (EGRF) family. Members of the ERBB family, including HER2, activate molecular cascades that stimulate proliferation and migration of cancer cells, as well as their resistance to the anticancer therapy. These proteins are often overexpressed and/or mutated in various cancer types and represent promising targets for the anti-cancer therapy. Currently, anti-HER2 drugs have been approved for the treatment of several types of solid tumors. HER2-specific therapy includes monoclonal antibodies and low-molecular weight inhibitors of tyrosine kinase receptors, such as lapatinib, neratinib, and pyrotinib. In addition to the activation of molecular pathways responsible for cell proliferation and survival under stress conditions, HER2 directly regulates programmed cell death. Here, we review the studies focused on the involvement of HER2 in various signaling pathways and its role in the regulation of apoptosis.

Genome-editing tools for stem cell biology.

Human pluripotent stem cells provide a versatile platform for regenerative studies, drug testing and disease modeling. That the expression of only four transcription factors, Oct4, Klf4, Sox2 and c-Myc (OKSM), is sufficient for generation of induced pluripotent stem cells (iPSCs) from differentiated somatic cells has revolutionized the field and also highlighted the importance of OKSM as targets for genome editing. A number of novel genome-editing systems have been developed recently. In this review, we focus on successful applications of several such systems for generation of iPSCs. In particular, we discuss genome-editing systems based on zinc-finger fusion proteins (ZFs), transcription activator-like effectors (TALEs) and an RNA-guided DNA-specific nuclease, Cas9, derived from the bacterial defense system against viruses that utilizes clustered regularly interspaced short palindromic repeats (CRISPR).

[NEGATIVE REGULATORS OF TUMOR SUPPRESSOR P53 IN THE CONTEXT OF ANTICANCER THERAPY].

P53 protein is considered to be the major tumor suppressor in human cells. Cancer cells do not survive if the p53-mediated signaling pathways function properly. However, about half of all malignancies still express wild type p53. One of the explanations to this is that p53 is suppressed by overexpression of p53-specific E3-ubiquitin ligases: Mdm2, MdmX, Pirh2 and Cop1. Pharmacological inhibition of protein-protein interactions between p53 and these negative regulators is a promising therapeutic approach to treat cancers retaining wild type p53. To date, a series of chemical inhibitors of p53 interactions with Mdm2 and MdmX E3-ubiquitin ligases have been discovered and characterized. Several of them are in the early stages of clinical trials. Despite this fact, their clinical efficacy may be hampered by a number of reasons, including tumor-specific expression of multiple isoforms of the target E3-ligases, which become inert to treatment with small molecules. This and other biochemical mechanisms of possible resistance of tumor cells with wild type p53 to small molecules against its negative regulators will be discussed in this review.

[TUMOR SUPPRESSOR p63 REGULATES EXPRESSION OF UBIQUITIN LIGASE Pirh2].

Transcription factor p63 is a member of the p53 protein family. Due to the high degree of structural similarity p53, p63, and p73 are known to have overlapping functions relating to cell cycle regulation, apoptosis and tumor transformation. Furthermore, p63 plays crucial role in epidermal tissue development and differentiation. Pirh2 (product of RCHY1 gene) is an E3 ubiquitin ligase modifying all three members of the p53 family resulting in their subsequent proteasomal degradation. Our results demonstrate that p63, similar to p53, is able to regulate expression levels of Pirh2. Importantly, Pirh2 expression is activated only by transcriptionally active isoform of p63--TAp63, but not the N-terminally truncated ΔNp63.