Drugs that Kill Cancer Stem-like Cells

The hallmarks of cancer include processes like self-sufficiency for growth signals, insensitivity to growth-inhibitory (anti-growth) signals, evasion of programmed cell death (apoptosis), unlimited replicative potential, sustained angiogenesis, and tissue invasion and metastasis (Hanahan & Weinberg, 2000). Recent research dictates that these definitions, while valid, ought to be enriched. That is, we should also consider tumours as a heterogeneous ‘collection of cancer cells’ with a hierarchy. This ‘hierarchical hypothesis’ tells us that tumours contain a minute (sometimes very small) sub-set of cells with distinct properties from the bulk of the tumour mass (D’Amour & Gage, 2002; Visvader & Lindeman, 2008; Visvader, 2009). These cells feature certain characteristics inherent to stem cells, including the capacity of self-renewal, asymmetric division and differentiation. They have also a very high propensity to form tumours. Therefore these cells are referred to as cancer stem cells (CSC) or cancer stem-like cells or, better, tumour-initiating cells (TICs). The terminology, while not too important, may be misleading though, since the term ‘cancer stem cells’ implies that we are dealing with true stem cells, which is not possible to reconcile with at this stage, perhaps even more so, since the origin of CSCs is not exactly known.Griffith Health, School of Medical ScienceFull Tex

The assembly factor SDHAF2 is dispensable for flavination of the catalytic subunit of mitochondrial complex II in breast cancer cells

Mitochondrial complex II or succinate dehydrogenase (SDH) is at the crossroads of oxidative phosphorylation and the tricarboxylic acid cycle. It has been shown that Sdh5 (SDHAF2/SDH5 in mammals) is required for flavination of the subunit Sdh1 (SDHA in human cells) in yeast. Here we demonstrate that in human breast cancer cells, SDHAF2/SDH5 is dispensable for SDHA flavination. In contrast to yeast, CRISPR-Cas9 nickase-mediated SDHAF2 KO breast cancer cells feature flavinated SDHA and retain fully assembled and functional complex II, as well as normal mitochondrial respiration. Our data show that SDHA flavination is independent of SDHAF2 in breast cancer cells, employing an alternative mechanism

Mitochondrial complex II, a novel target for anti-cancer agents

With the arrival of the third millennium, in spite of unprecedented progress in molecular medicine, cancer remains as untamed as ever. The complexity of tumours, dictating the potential response of cancer cells to anti-cancer agents, has been recently highlighted in a landmark paper by Weinberg and Hanahan on hallmarks of cancer [1]. Together with the recently published papers on the complexity of tumours in patients and even within the same tumour (see below), the cure for this pathology seems to be an elusive goal. Indisputably, the strategy ought to be changed, searching for targets that are generally invariant across the landscape of neoplastic diseases. One such target appears to be the mitochondrial complex II (CII) of the electron transfer chain, a recent focus of research. We document and highlight this particularly intriguing target in this review paper and give examples of drugs that use CII as their molecular target. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease. (C) 2012 Elsevier B.V. All rights reserved

Mitochondrial complex II: at the crossroads

Mitochondrial complex II (CII), also called succinate dehydrogenase (SDH), is a central purveyor of the reprogramming of metabolic and respiratory adaptation in response to various intrinsic and extrinsic stimuli and abnormalities. In this review we discuss recent findings regarding SDH biogenesis, which requires four known assembly factors, and modulation of its enzymatic activity by acetylation, succinylation, phosphorylation, and proteolysis. We further focus on the emerging role of both genetic and epigenetic aberrations leading to SDH dysfunction associated with various clinical manifestations. This review also covers the recent discovery of the role of SDH in inflammation-linked pathologies. Conceivably, SDH is a potential target for several hard-to-treat conditions, including cancer, that remains to be fully exploited

Liposomal Delivery of miR-34b-5p Induced Cancer Cell Death in Thyroid Carcinoma

This study aims to determine the functional roles of microRNA-34b-5p (miR-34b) in the suppression of anaplastic thyroid carcinoma. We used hydration-of-freeze-dried-matrix (HFDM) formulated liposomes (liposome-loaded miR-34b) for effective delivery of miR-34b to anaplastic thyroid carcinoma in vitro and in vivo. Real time polymerase chain was used to determine the level of miR-34b. Immunocytochemistry, Western blot and ELISA were carried out to determine the effect of this manipulation on VEGF-A expression. In addition, an in vivo xenotransplantation mouse model was used to investigate the functional roles of overexpression of miR-34b in the carcinoma. In anaplastic thyroid carcinoma cells, miR-34b expression was low and significant overexpression (p < 0.05) was noted following transfection with liposome-loaded miR-34b. The miR-34b overexpressed thyroid carcinoma cell lines showed reduction in VEGF-A protein expression, decreased cell proliferation, decreased wound healing, reduced cell cycle progression and increased apoptosis (p < 0.05). In in vivo experiments, when compared to control groups, smaller tumours formed upon intravenous administration of liposome-loaded miR-34b. To conclude, the current study confirmed the tumour suppressor properties of miR-34b via VEGF-A regulation in anaplastic thyroid carcinoma. In addition, delivery of miR-34b using cationic liposome could be a useful therapeutic strategy for targeting therapy in the carcinoma

Molecular basis for 5-carboxycytosine recognition by RNA polymerase II elongation complex.

DNA methylation at selective cytosine residues (5-methylcytosine (5mC)) and their removal by TET-mediated DNA demethylation are critical for setting up pluripotent states in early embryonic development. TET enzymes successively convert 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), with 5fC and 5caC subject to removal by thymine DNA glycosylase (TDG) in conjunction with base excision repair. Early reports indicate that 5fC and 5caC could be stably detected on enhancers, promoters and gene bodies, with distinct effects on gene expression, but the mechanisms have remained elusive. Here we determined the X-ray crystal structure of yeast elongating RNA polymerase II (Pol II) in complex with a DNA template containing oxidized 5mCs, revealing specific hydrogen bonds between the 5-carboxyl group of 5caC and the conserved epi-DNA recognition loop in the polymerase. This causes a positional shift for incoming nucleoside 5'-triphosphate (NTP), thus compromising nucleotide addition. To test the implication of this structural insight in vivo, we determined the global effect of increased 5fC/5caC levels on transcription, finding that such DNA modifications indeed retarded Pol II elongation on gene bodies. These results demonstrate the functional impact of oxidized 5mCs on gene expression and suggest a novel role for Pol II as a specific and direct epigenetic sensor during transcription elongation