Special Issue "Programmed Cell Death and Apoptosis"

Guest Editor
Prof. Dr. Anthony Lemarié
Department of Experimental Therapeutics, Inserm U1037 Toulouse Cancer Research Center & Institut Claudius Regaud, 20-24 rue du pont St Pierre, 31052 Toulouse cedex, France
E-Mail: lemarie.anthony@claudiusregaud.fr

Dear Colleagues,

Apoptosis is considered as an essential physiological process in eukaryotes for development, tissue homeostasis, wound healing or immune response. Moreover, apoptosis appears as a key player in physiopathological deregulations, since sustained apoptotic cell death characterizes ischemic and degenerative diseases as well as toxicological responses and since impaired cell death confers to cells and tissues a hyperproliferative phenotype as observed in cancer cells or autoimmune diseases. This special issue is dedicated to bring to light some recent developments in the cell death area and to further present some comprehensive reviews on specific “hot” spots in the apoptotic field. In particular, it is of major interest to present the different types of programmed cell death, such as apoptosis, autophagic cell death, necroptosis and secondary necrosis, mitotic catastrophe or senescence and to depict their specific mechanisms and crossovers. The physiopathological context of each process is of particular importance. In addition, the different upstream early events leading to cell death signalling remain to be fully deciphered, notably the role of oxidative stress, ionic homeostasis, metabolic stress signals (e.g. hypoxia), DNA damages and microRNAs.
Concerning apoptosis, several aspects have to be addressed as the dependency on the caspase proteases, the involvement of extrinsic (death receptors) and intrinsic (mitochondrial) pathways and the role of the endoplasmic reticulum pathway. Finally, it would be of great interest to focus on the pro-survival vs pro-apoptotic regulation in tumour cells and during anticancer treatments (either chemo or radiotherapy), particularly towards several emerging targets such as cancer stem cells or circulating cancer cells.

Research articles, review articles as well as communications are invited.

Prof. Dr. Anthony Lemarié
Guest Editor

Submission

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• apoptosis
• autophagic cell death
• cancer cell death
• caspase-dependent and independent apoptosis
• cellular and mitochondrial homeostasis
• cell death signalling
• mitochondrial and death receptor pathways
• mitotic catastrophe
• oxidative stress and antioxidants
• programmed cell death

Feature Paper:

Title: Implication of Tumor Microenvironment in Chemoresistance: Tumor-Associated Cells (Fibroblasts, Mesenchymal Stem Cells or Macrophages) Protect Tumor Cells from Apoptosis
Authors: Magali Castells ^1,2, Benoît Thibault ^1,2 and Bettina Couderc ^1,2
Affiliations: ¹ EA4553, Institut Claudius Regaud, F-31062 Toulouse, France
² University of Toulouse III, F-31052 Toulouse, France; E-Mail: couderc.bettina@claudiusregaud.fr
Abstract: Tumoral development is mainly associated with the accumulation of multiple genetic and epigenetic alterations in the tumor cells which pave the way for the transformation of a normal cell into a cancer cell and of a chemosensitive cell to a chemoresistant one by influencing the uptake, metabolism, or export of drugs from single cells. However, numerous reports reveal the complexity of tumors, composed of genetically altered tumor cells within a heterogeneous population of stromal cells, the tumoral microenvironment. The stromal cells (fibroblasts, endothelial or mesothelial cells, adipocytes or adipose tissue-derived stromal cells, immune cells and bone marrow-derived stem cells) enhance tumoral progression and development through the secretion of proteases and growth or pro-angiogenic factors. The secretion of proteases increasing the invasive potential of the tumoral cells promotes tumor progression. Stromal cells could be also involved in the chemoresistance acquisition by tumor cells. This could be acquired by i) contact between tumor cells and stromal cells enabling the tumor cells to capture patches of the stromal membrane through “oncologic trogocytosis” thereby acquiring their functional P-gp proteins and developing chemoresistance. ii) cell–cell and cell–matrix interactions influencing the cancer cells sensitivity to apoptosis and affect drug resistance. iii) the cross talk between stromal cells and tumor cells through paracrine factors secreted by the two cells population iv) the generation of specific niches within the tumor microenvironment containing a subpopulations of tumors cells that affords a survival advantage following initial drug exposure and may facilitate the acquisition of acquired drug resistance. This review will focus on the implication of each member of the heterogeneous population of stromal cells in conferring resistance to cytotoxics and physiological mediators of cell death. The potential therapeutic implications of abolishing stromal protective mechanisms to overcome drug resistance will be discussed.

Type of Paper: Review
Title: Selenium Compounds, Apoptosis and Other Types of Cell Death: An Overview for Cancer Therapy
Authors: Carmen Sanmartín ^*, Daniel Plano and Juan Antonio Palop
Affiliation: Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain; E-Mail: sanmartin@unav.es (C.S.)
Abstract: Selenium (Se) is an essential trace element involved in different physiological functions of human body and plays a role in cancer prevention and treatment. Induction of apoptosis is considered an important cellular event that can account for the cancer preventive effects of Se. The mechanism of Se-induced apoptosis are associated with the chemical forms of Se and their metabolism so as the type of cancer studied. So, some seleno compounds, such as SeO₂ involve the activation of caspase-3 while sodium selenite induced apoptosis in the absence of the activation of caspases. Modulation of mitochondrial function have been reported to play a key role in the regulation of apoptosis and to also be one of the targets of Se compounds. Another mechanisms for apoptosis induction are the modulation of glutathione and reactive oxygen species levels, that may function as intracellular messengers to regulate signaling pathways, or the regulation of kinase among others. Emerging evidence indicates the overlaps between the apoptosis and other types of cell death for example autophagy. In this review we focuse in the different processes of cell death induced by selenium compounds for cancer treatment and prevention.

Type of Paper: Article
Title: Arsenic Trioxide Inhibits Cell Growth and Induced Apoptosis Through Inactivation of Notch Signaling Pathway in Breast Cancer
Authors: Jun Xia ¹, Youjian Li ¹, Zhiwen Chen ¹, Lucio Miele ², Fazlul H Sarkar ³ and Zhiwei Wang ^1,4
Affiliations: ¹ Department of Biochemistry & Molecular Biology, Bengbu Medical College, Anhui, 233000, China
² University of Mississippi Cancer Institute, Jackson, MS 39216, USA
³ Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
⁴Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, MA 02215, USA; E-Mail: zwang6@bidmc.harvard.edu
Abstract: Arsenic trioxide has been reported to inhibit cell growth and induce cellular apoptotic death in many human cancer cells including breast cancer. However, the precise molecular mechanisms underlying antitumor activity of arsenic trioxide are still largely unknown. In the present study, we assessed the effects of arsenic trioxide on cell viability and apoptosis in breast cancer. For mechanistic studies, we used multiple cellular and molecular approaches such as MTT assay, apoptosis ELISA assay, gene transfection, Real-time RT-PCR, Western blotting, and invasion assay. For the first time, we found a significant reduction in cell viability in arsenic trioxide-treated cells in a dose- and time-dependent manner, which was consistent with induction of apoptosis and also associated with down-regulation of Notch-1 and its target genes. Taken together, our findings provide evidence showing that the down-regulation of Notch-1 by arsenic trioxide could be an effective approach, which will cause down-regulation of Bcl-2, and NF-B, resulting in the inhibition of cell growth and invasion as well as induction of apoptosis. These results suggest that antitumor activity of arsenic trioxide is mediated through a novel mechanism involving inactivation of Notch-1 and its target genes. We also suggest that arsenic trioxide could be further developed as a potential therapeutic agent for the treatment of breast cancer.

Type of Paper: Article
Title: The Tricyclodecan-9-yl-xanthogenate D609 Triggers Ceramide Increase and Enhances FasL-induced Caspase-dependent and –independent Cell Death in T lymphocytes
Authors: D. Milhas ¹ and B. Segui ²
Affiliations: ¹ INSERM UMR1037, Centre de Recherches en Cancérologie de Toulouse, Equipe 4, BP84225, 31432 Toulouse Cedex 4, France
² Faculté des Sciences Pharmaceutiques, Service de Biologie Cellulaire, Hématologie et Immunologie, Université Paul Sabatier (Toulouse III), 35 Chemin des Maraîchers, 31062, Toulouse, France; E-Mail: bruno.segui@inserm.fr
Abstract: D609 is known to modulate death receptor-induced ceramide generation and cell death. We show that in Jurkat cells, non-toxic D609 concentrations inhibit sphingomyelin synthase and, to a lesser extent, glucosylceramide synthase, and transiently increase intracellular ceramide level. D609 significantly enhanced FasL-induced caspase activation and apoptosis. D609 stimulated FasL-induced cell death in caspase-8-deficient Jurkat cells indicating that D609 acts downstream of caspase-8. At high FasL concentration (500 ng/mL), cell death was significantly, but not completely, inhibited by zVAD-fmk, a broad-spectrum caspase inhibitor, indicating that FasL can activate both caspase-dependent and –independent cell death signaling pathways. FasL-induced caspase activation was abolished by zVAD-fmk whereas ceramide production was only partially impaired. D609 enhanced caspase-independent ceramide increase and cell death in response to FasL. Also, D609 overcame zVAD-fmk-conferred resistance to a FasL concentration as low as 50 ng/mL and bypassed Rip deficiency. Mitochondrial events were likely involved since Bcl-xL over-expression impaired D609 effects. In PHA-activated human T lymphocytes, D609 enhanced FasL-induced cell death in the presence or absence of zVAD-fmk. Altogether, our data strongly indicate that the inhibition of ceramide conversion to complex sphingolipids by D609 is accompanied by an enhancement of FasL-induced caspase-dependent and –independent cell death in T lymphocytes.