Mariko Nakano-Okuno

EZH2 protects glioma stem cells from radiation-induced cell death in a MELK/FOXM1-dependent manner.

Summary Glioblastoma (GBM)-derived tumorigenic stem-like cells (GSCs) may play a key role in therapy resistance. Previously, we reported that the mitotic kinase MELK binds and phosphorylates the oncogenic transcription factor FOXM1 in GSCs. Here, we demonstrate that the catalytic subunit of Polycomb repressive complex 2, EZH2, is targeted by the MELK-FOXM1 complex, which in turn promotes resistance to radiation in GSCs. Clinically, EZH2 and MELK are coexpressed in GBM and significantly induced in postirradiation recurrent tumors whose expression is inversely correlated with patient prognosis. Through a gain-and loss-of-function study, we show that MELK or FOXM1 contributes to GSC radioresistance by regulation of EZH2. We further demonstrate that the MELK-EZH2 axis is evolutionarily conserved in Caenorhabditis elegans. Collectively, these data suggest that the MELK-FOXM1-EZH2 signaling axis is essential for GSC radioresistance and therefore raise the possibility that MELK-FOXM1-driven EZH2 signaling can serve as a therapeutic target in irradiation-resistant GBM tumors.

Multi-kinase inhibitor C1 triggers mitotic catastrophe of glioma stem cells mainly through MELK kinase inhibition.

Glioblastoma multiforme (GBM) is a highly lethal brain tumor. Due to resistance to current therapies, patient prognosis remains poor and development of novel and effective GBM therapy is crucial. Glioma stem cells (GSCs) have gained attention as a therapeutic target in GBM due to their relative resistance to current therapies and potent tumor-initiating ability. Previously, we identified that the mitotic kinase maternal embryonic leucine-zipper kinase (MELK) is highly expressed in GBM tissues, specifically in GSCs, and its expression is inversely correlated with the post-surgical survival period of GBM patients. In addition, patient-derived GSCs depend on MELK for their survival and growth both in vitro and in vivo. Here, we demonstrate evidence that the role of MELK in the GSC survival is specifically dependent on its kinase activity. With in silico structure-based analysis for protein-compound interaction, we identified the small molecule Compound 1 (C1) is predicted to bind to the kinase-active site of MELK protein. Elimination of MELK kinase activity was confirmed by in vitro kinase assay in nano-molar concentrations. When patient-derived GSCs were treated with C1, they underwent mitotic arrest and subsequent cellular apoptosis in vitro, a phenotype identical to that observed with shRNA-mediated MELK knockdown. In addition, C1 treatment strongly induced tumor cell apoptosis in slice cultures of GBM surgical specimens and attenuated growth of mouse intracranial tumors derived from GSCs in a dose-dependent manner. Lastly, C1 treatment sensitizes GSCs to radiation treatment. Collectively, these data indicate that targeting MELK kinase activity is a promising approach to attenuate GBM growth by eliminating GSCs in tumors.

Ethics of iPSC-based clinical research for age-related macular degeneration: patient-centered risk-benefit analysis.

The opportunity to undergo an induced pluripotent stem cell-based autologous transplant can strike patients as a chance for a cure from a debilitating condition with few options for respite. However, when clinical studies of this caliber present themselves, patients and researchers, each with their own set of motives, may find it difficult to take a balanced approach to evaluating them. We present a patient-centered risk-benefit analysis of the iPSC-based clinical research currently underway in Japan, including a survey of in vitro and in vivo tests that support this project, an in-depth discussion of risks, and further elucidation of considerations patients may wish to consider. The arguments presented will assist patients in undertaking a more informed decision-making process.

Philosophical Foundations of Utilitarianism

We have finally come to the point of elucidating the basic structure of utilitarianism by making the most of Sidgwick’s analyses and arguments. In The Methods of Ethics, utilitarianism gets its theoretical foundations through philosophical inquiry and gains external support from a careful examination of common-sense morality. In this chapter we will examine both ways of verifying utilitarianism. We will see that the previously described conceptual analyses and the three intuitive fundamental principles, plus the proof of hedonism (to be explained later in this chapter), construct the essential components of utilitariaism, namely consequentialism and the principle of maximizing the sum total of people’s pleasure.

The Three Fundamental Principles

These three fundamental principles are called ‘real ethical axioms — intuitive propositions of real clearness and certainty’ (ME Bk. 3 Ch. 13 p. 373), ‘self-evident moral principles of real significance’ (ME p. 379), or ‘absolute practical principles’ (ibid.). They are principles which are apprehended by philosophical intuition, and which will provide guidance for actions that ought to be done.

Reconciling the Dualism of Practical Reason

The last theoretical problem we will deal with in this book is Sidgwick’s dualism of practical reason, or the fundamental conflict between egoism and utilitarianism. According to Sidgwick, utilitarianism and egoism have equally solid theoretical bases; and yet completely different, and possibly conflicting, courses of action can be prescribed by these two different views.

An Approach not Appealing to Moral Intuition

Sidgwick used his philosophical intuition to reach the three fundamental principles, from which he developed his argument about the foundation of utilitarianism. The reason why Sidgwick believed we could rely on these three ‘intuitive’ principles, while dismissing perceptional and dogmatic intuitionism, was because these three principles use clear and definite terms, because their validity can be repeatedly confirmed by reflection, and because these are presumably accepted by most or all people regardless of the differences in the ethical views they usually hold. However, we may question whether his ‘philosophical intuition’ is really common to us all, and on what grounds we can say so. In replying to this problem, the moral philosopher Richard Mervyn Hare (1919–2002) attempted to develop an ethical theory by appealing only to logic and facts, which we would surely accept as our common basis, and which we can ascertain as being universally valid by observing how we actually behave and how we actually use our language. His argument is also important in that it led him to advocate a version of utilitarianism, taking quite a different route from Sidgwick’s. In this chapter, we will examine Hare’s argument for utilitarianism and compare it with Sidgwick’s analyses.

An Overview of The Methods of Ethics

It is evident that Henry Sidgwick was a utilitarian, from his writings and from the testimony of people closest to him. For example, in The Elements of Politics, Sidgwick asserts that there is a general assent among people that the ultimate criterion for determining right and wrong in legislation is a utilitarian one (Sidgwick 1891, Ch. 3 Sec. 2 pp. 34–5; 3rd edn, 1908, pp. 37–8). In his 1897 essay, he also states that ‘for those who, like myself, hold that the only true basis for morality is a utilitarian basis’ (‘Public Morality’, in Sidgwick 1898, p. 63).

Interpersonal Comparison and Maximization

In either the preference or the happiness version, utilitarianism is a theory that requires the comparison of people’s preferences in making a moral judgment. That is, it seeks to determine what one ought to do by comparing feasible courses of action and by balancing people’s preferences regarding the states of affairs that each alternative course of action will bring about.1 Theoretically, Hare’s special version of utilitarianism is designed to dispense with such an interpersonal comparison, since in his theory all the preferences that are balanced are preferences of the person who is making a moral judgment. All of them are his own preferences, including those which he newly acquired by representing others’ preferences to himself and which have the same quality and intensity as other people’s actual preferences. We will return to Hare’s maneuver later. Here, however, let us take utilitarianism to be a theory that requires interpersonal comparisons of preferences, including those of oneself and others. When we pursue this line, we encounter another problem of utilitarianism, which is how to compare people’s preferences and integrate them into a moral judgment. We also have the related problem of how to compare a present preference with a future preference. Let us assume, however, that we are discussing both types of problems, that is, the inter-personal and the inter-temporal comparisons of preferences, when we talk about comparing people’s preferences in the argument below.

The Scope of Ethics

Ethics as Sidgwick understands it is ‘the science or study of what is right or what ought to be, so far as this depends upon the voluntary action of individuals’ (ME p. 4). Science here means a systematic study, which seeks to attain precise knowledge (see ME p. 1). But unlike such sciences as psychology or sociology, ethics deals not with mere facts, but with norms of action, expressed in terms of ‘ought’ or ‘right’. Some believe that ethics also deals with virtues, or a moral evaluation of a person’s character, rather than his or her actions; but one’s character is known to us only through his or her acts; and we usually do not separate an evaluation of someone’s character from that of his or her behavior (ME Bk. 1 Ch. 9 p. 113 fn. 1). Therefore, the primary subject of ethics is considered to be an individual’s actions. Another study that treats norms is politics; but unlike politics, which deals with the decision-making of a government, ethics deals with the actions of an individual. Thus Sidgwick’s primary concern is with individual decision-making, but he does not distinguish between individual acts done in public and those done in private.1