Suicide gene

About: Suicide gene is a research topic. Over the lifetime, 2970 publications have been published within this topic receiving 119195 citations.

Mechanisms and genes of cellular suicide

Abstract: Apoptosis is a morphologically distinct form of programmed cell death that plays a major role during development, homeostasis, and in many diseases including cancer, acquired immunodeficiency syndrome, and neurodegenerative disorders. Apoptosis occurs through the activation of a cell-intrinsic suicide program. The basic machinery to carry out apoptosis appears to be present in essentially all mammalian cells at all times, but the activation of the suicide program is regulated by many different signals that originate from both the intracellular and the extracellular milieu. Genetic studies in the nematode Caenorhabditis elegans and in the fruit fly Drosophila melanogaster have led to the isolation of genes that are specifically required for the induction of programmed cell death. At least some components of the apoptotic program have been conserved among worms, insects, and vertebrates.

Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy.

Abstract: Apoptosis or programmed cell death is a key regulator of physiological growth control and regulation of tissue homeostasis. One of the most important advances in cancer research in recent years is the recognition that cell death mostly by apoptosis is crucially involved in the regulation of tumor formation and also critically determines treatment response. Killing of tumor cells by most anticancer strategies currently used in clinical oncology, for example, chemotherapy, γ-irradiation, suicide gene therapy or immunotherapy, has been linked to activation of apoptosis signal transduction pathways in cancer cells such as the intrinsic and/or extrinsic pathway. Thus, failure to undergo apoptosis may result in treatment resistance. Understanding the molecular events that regulate apoptosis in response to anticancer chemotherapy, and how cancer cells evade apoptotic death, provides novel opportunities for a more rational approach to develop molecular-targeted therapies for combating cancer.

In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors

Abstract: Direct in situ introduction of exogenous genes into proliferating tumors could provide an effective therapeutic approach for treatment of localized tumors. Rats with a cerebral glioma were given an intratumoral stereotaxic injection of murine fibroblasts that were producing a retroviral vector in which the herpes simplex thymidine kinase (HS-tk) gene had been inserted. After 5 days during which the HS-tk retroviral vectors that were produced in situ transduced the neighboring proliferating glioma cells, the rats were treated with the anti-herpes drug ganciclovir. Gliomas in the ganciclovir- and vector-treated rats regressed completely both macroscopically and microscopically. This technique exploits what was previously considered to be a disadvantage of retroviral vectors--that is, their inability to transfer genes into nondividing cells. Instead, this feature of retroviruses is used to target gene delivery to dividing tumor cells and to spare nondividing neural tissue.

Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κB

Abstract: The abilities of NF-κB to promote cell proliferation, suppress apoptosis, promote cell migration, and suppress differentiation apparently have been co-opted by cellular and viral oncoproteins to promote oncogenesis (Figure ​(Figure2).2). Direct evidence, using both in vitro and in vivo models, indicates that NF-κB is required for oncogenesis, probably at multiple levels. NF-κB likely plays an important role in the early events of oncogenesis, possibly functioning primarily in protecting against transformation-associated apoptosis. In most late-stage tumor cells, classic NF-κB (the p50-p65 heterodimer) is clearly not the only survival factor, because its inhibition does not induce apoptosis in many of these tumor cells. This observation suggests that other events have occurred to upregulate NF-κB–independent cell survival pathways. However, clearly some cancer cells depend on NF-κB for their survival. NF-κB also can contribute to cell progression by transcriptionally upregulating cyclin D1 with corresponding hyperphosphorylation of the tumor suppressor protein Rb. The induction of NF-κB–controlled proliferation may correlate with loss of differentiation in certain settings (47), which may promote oncogenesis. NF-κB is known to regulate certain genes associated with metastasis, such as matrix metalloproteinase 9, tissue plasminogen activator, and ICAM-1. Thus, a more relevant role for NF-κB in later-stage oncogenesis may be to promote metastasis and angiogenesis. Although many tumor cells display some level of constitutive nuclear NF-κB, higher levels of NF-κB and the transcriptional potential of NF-κB can be further enhanced in response to certain types of chemotherapy. Consistent with this, inhibition of NF-κB in parallel with certain (but apparently not all) chemotherapy treatments strongly enhances the apoptotic potential of the chemotherapy. This observation indicates that NF-κB plays an important role in inducible chemoresistance and establishes NF-κB inhibition as a new adjuvant approach in chemotherapy.

The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

Abstract: The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1(-/Δ) mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1(-/∆) mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.