Stimulation of the catalytic activity of poly(ADP-ribosyl) transferase by transcription factor Yin Yang 1

AbstractThe transcriptional regulator Yin Yang 1 (YY1) has previously been demonstrated to physically interact with poly(ADP-ribosyl) transferase (ADPRT). This nuclear enzyme catalyzes the synthesis of ADP-ribose polymers and their attachment to target proteins. It is reported here that YY1 associates preferably with the extensively auto(ADP-ribosyl)ated form of ADPRT, but not with deproteinized ADP-ribose polymers. In the presence of YY1 the catalytic rate of ADPRT is enhanced about 10-fold. This stimulation is in part due to modification of YY1, thus serving as a substrate of the reaction. In addition, automodification of ADPRT is also substantially increased. The activation by YY1 is most pronounced at low concentrations of ADPRT suggesting that the presence of YY1 may either facilitate the formation of catalytically active dimers of ADPRT or lead to the occurrence of active heterooligomers. The potential significance of these observations was verified by analyzing the activity of ADPRT in HeLa nuclear extracts. The endogenous enzyme exhibited an about 10-fold higher activity as compared to the isolated recombinant protein. It is likely that the heat-stable transcription factor YY1 contributed to the increased activity of ADPRT detected in the nuclear extracts, because heated extracts had a similar stimulatory effect on isolated ADPRT as isolated YY1 used at comparable concentrations. It is concluded that YY1 may be an important regulator of ADPRT and, therefore, could support the function of ADPRT to facilitate DNA repair

Are Aspects of Integrative Concepts Helpful to Improve Pancreatic Cancer Therapy?

Numerous clinical studies have been conducted to improve the outcomes of patients suffering from pancreatic cancer. Different approaches using targeted therapeutic strategies and precision medicine methods have been investigated, and synergies and further therapeutic advances may be achieved through combinations with integrative methods. For pancreatic tumors, a particular challenge is the presence of a microenvironment and a dense stroma, which is both a physical barrier to drug penetration and a complex entity being controlled by the immune system. Therefore, the state of immunological tolerance in the tumor microenvironment must be overcome, which is a considerable challenge. Integrative approaches, such as hyperthermia, percutaneous irreversible electroporation, intra-tumoral injections, phytotherapeutics, or vitamins, in combination with standard-oncological therapies, may potentially contribute to the control of pancreatic cancer. The combined application of standard-oncological and integrative methods is currently being studied in ongoing clinical trials. An actual overview is given here

Mistletoe and Immunomodulation: Insights and Implications for Anticancer Therapies

In early tumor development, cancer cells develop a plethora of strategies to escape surveillance from the adaptive and innate immune system. Cancer immunotherapies, in particular immune checkpoint inhibitors, are becoming a highly promising cancer therapeutic approach that has remarkable increased progress in combating various cancer types. Unfortunately, their mechanisms of action induce some complications, such as inflammatory reactions and immune-related adverse events. In the management of side effects during anticancer therapy, complementary and integrative therapy approaches are becoming of growing interest. Particularly, mistletoe, Viscum album L. (VA), has a long traditional history of about 100 years as an add-on therapy of cancer treatment in German-speaking countries. Besides antitumoral and quality of life-promoting activities, VA applications reduce side effects of modern conventional anticancer therapies and exert immunomodulatory characteristics. As these properties may provide a good basis for a combination with modern oncological therapies, the biological activities of VA applications and mechanisms involved have to be understood. In this review, the impact of VA compounds on different cellular pathways and immunological reactions in the fight against cancerous cells is discussed