Caspase-mediated cleavage of β-catenin precedes drug-induced apoptosis in resistant cancer cells (original) (raw)
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International journal of oncology, 2018
Tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL) exhibits antitumor activity in various types of tumor cell and tumor‑bearing animals. However, acquired TRAIL resistance is a common issue that restricts its clinical application. Previous studies have revealed that β‑catenin is associated with TRAIL resistance in melanoma and colorectal tumors. In the present study, an acquired‑resistance non‑small‑cell lung cancer (NSCLC) cell line (H460‑TR) was established from parental TRAIL‑sensitive H460 cells using a gradient ascent model (8‑256 ng/ml TRAIL). Cellular FADD‑like interleukin‑1β converting enzyme inhibitory protein and Mcl‑1 were upregulated and the cell surface distribution of death receptor (DR)4 and DR5 was downregulated in H460‑TR cells compared with the parental H460 cells. The results of reverse transcription‑quantitative polymerase chain reaction and western blot analysis indicated that H460 cells expressed increased levels of β‑catenin and were more sensitiv...
Apoptosis: mechanisms and implications for cancer therapeutics
Targeted Oncology, 2006
Apoptosis, or programmed cell death, is essential for many physiological and pathological processes. Apoptosis results from an orderly activation of several cysteine proteases called caspases, which can be classically triggered by two upstream pathways: the intrinsic and extrinsic pathways. Deregulation of apoptosis is essential for tumor growth and a hallmark of cancer cells. In the recent years, many key elements of the apoptotic process have been identified and have become strategic targets for anticancer therapy. The novel approaches that target the apoptotic pathway may have either a direct proapoptotic effect or alternatively may sensitize cancer cells to other cytotoxics. This review describes the major elements of the apoptotic process, with a special focus of the tight interactions between the extrinsic and intrinsic pathways, and summarizes some of the most promising implications for cancer therapeutics.
2001
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a new cytokine that was proposed to specifically induce apoptosis of cancer cells. In tumor cells that are resistant to the cytokine, subtoxic concentrations of chemotherapeutic drugs can restore the response to TRAIL. The present study further explores the mechanisms that determine tumor cell sensitivity to TRAIL by comparing four human colon carcinoma cell lines. We show that colon cancer cell sensitivity to TRAIL-induced apoptosis and cytotoxicity correlates with the expression of the death receptors TRAIL-R1 and TRAIL-R2 at the cell surface, as determined by flow cytometry, whereas the two decoy receptors TRAIL-R3 and TRAIL-R4 can be detected only in permeabilized cells. Clinically relevant concentrations of cisplatin and doxorubicin sensitize the most resistant colon cancer cell lines to TRAIL-induced cell death without modifying the expression nor the localization of TRAIL receptors in these cells. TRAIL induces the activation of procaspase-8 and triggers caspase-dependent apoptosis of colon cancer cells. Cytotoxic drugs lower the signaling threshold required for TRAIL-induced procaspase-8 activation. In turn, caspase-8 cleaves Bid, a BH3 domain-containing proapoptotic molecule of the Bcl-2 family, and activates effector caspases. Together, these data indicate that chemotherapeutic drugs sensitize colon tumor cells to TRAIL-mediated caspase-8 activation and apoptosis. . The abbreviations used are: TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; TNF, tumor necrosis factor; mAb, monoclonal antibody; FADD, Fas-associated death domain; z-VAD-fmk, z-Val-Ala-Asp-fluoromethyl ketone; z-IETD-fmk, z-Ile-Glu-Thr-Asp-fluoromethylketone; z-DEVD-fmk, z-Asp-Glu-Val-Asp-fluoromethylketone; IETD-AFC, IETD-7-amino-4-tri-fluoromethylcoumarine; DEVD-AMC, DEVD-7-aminomethylcourmarine; PARP, poly(ADP-ribose) polymerase.
Cancer Research, 2001
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a new cytokine that was proposed to specifically induce apoptosis of cancer cells. In tumor cells that are resistant to the cytokine, subtoxic concentrations of chemotherapeutic drugs can restore the response to TRAIL. The present study further explores the mechanisms that determine tumor cell sensitivity to TRAIL by comparing four human colon carcinoma cell lines. We show that colon cancer cell sensitivity to TRAIL-induced apoptosis and cytotoxicity correlates with the expression of the death receptors TRAIL-R1 and TRAIL-R2 at the cell surface, as determined by flow cytometry, whereas the two decoy receptors TRAIL-R3 and TRAIL-R4 can be detected only in permeabilized cells. Clinically relevant concentrations of cisplatin and doxorubicin sensitize the most resistant colon cancer cell lines to TRAIL-induced cell death without modifying the expression nor the localization of TRAIL receptors in these cells. TRAIL induces the activation of procaspase-8 and triggers caspase-dependent apoptosis of colon cancer cells. Cytotoxic drugs lower the signaling threshold required for TRAIL-induced procaspase-8 activation. In turn, caspase-8 cleaves Bid, a BH3 domain-containing proapoptotic molecule of the Bcl-2 family, and activates effector caspases. Together, these data indicate that chemotherapeutic drugs sensitize colon tumor cells to TRAIL-mediated caspase-8 activation and apoptosis. . The abbreviations used are: TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; TNF, tumor necrosis factor; mAb, monoclonal antibody; FADD, Fas-associated death domain; z-VAD-fmk, z-Val-Ala-Asp-fluoromethyl ketone; z-IETD-fmk, z-Ile-Glu-Thr-Asp-fluoromethylketone; z-DEVD-fmk, z-Asp-Glu-Val-Asp-fluoromethylketone; IETD-AFC, IETD-7-amino-4-tri-fluoromethylcoumarine; DEVD-AMC, DEVD-7-aminomethylcourmarine; PARP, poly(ADP-ribose) polymerase.
Apoptosis and cancer: insights molecular mechanisms and treatments
2015
Apoptosis is a form of cell death that permits the removal of damaged, senescent or unwanted cells in multicellular organisms, without damage to the cellular microenvironment, but it is also involved in a wide range of pathological processes, including cancer. An understanding of the underlying mechanism of apoptosis is important as it plays a pivotal role in the pathogenesis of many diseases. Defective apoptosis represents a major causative factor in the development and progression of cancer. The majority of chemotherapeutic agents, as well as radiation, utilize the apoptotic pathway to induce cancer cell death. Recent knowledge on apoptosis has provided the basis for novel targeted therapies that exploit apoptosis to treat cancer by acting in the extrinsic/intrinsic pathway. Defects can occur at any point along these pathways, leading to malignant transformation of the affected cells, tumour metastasis and resistance to anticancer drugs. In particular, this review provides references concerning the apoptotic molecules, their interactions, the mechanisms involved in apoptosis resistance, and also the modulation of apoptosis for the treatment of cancer. Despite being the cause of problem, apoptosis plays an important role in the treatment of cancer as it is a popular target of many treatment strategies.
2003
Tumor necrosis factor-related apoptosis-inducing-ligand (TRAIL/ Apo-2 ligand) induces apoptosis in the majority of cancer cells without appreciable effect in normal cells. Here, we report the effects of TRAIL on apoptosis in several human breast cancer cell lines, primary memory epithelial cells, and immortalized nontransformed cell lines, and we examine whether chemotherapeutic agents augment TRAIL-induced cytotoxicity in breast cancer cells in vitro and in vivo. TRAIL induced apoptosis with different sensitivities, and the majority of cancer cell lines were resistant to TRAIL. The chemotherapeutic drugs (paclitaxel, vincristine, vinblastine, etoposide, camptothecin, and Adriamycin) induced death receptors (DRs) TRAIL receptor 1/DR4 and TRAIL receptor 2/DR5, and successive treatment with TRAIL resulted in apoptosis of both , and -8 activation. The sequential treatment of nude mice with chemotherapeutic drugs followed by TRAIL induced caspase-3 activity and apoptosis in xenografted tumors. Complete eradication of established tumors and survival of mice were achieved without detectable toxicity. Thus, the sequential administration of chemotherapeutic drugs followed by TRAIL may be used as a new therapeutic approach for cancer therapy.
Apoptosis: a relevant tool for anticancer therapy
Annals of Oncology, 2006
Apoptosis is a form of cell death that permits the removal of damaged, senescent or unwanted cells in multicellular organisms, without damage to the cellular microenvironment. Defective apoptosis represents a major causative factor in the development and progression of cancer. The majority of chemotherapeutic agents, as well as radiation, utilize the apoptotic pathway to induce cancer cell death. Resistance to standard chemotherapeutic strategies also seems to be due to alterations in the apoptotic pathway of cancer cells. Recent knowledge on apoptosis has provided the basis for novel targeted therapies that exploit apoptosis to treat cancer. These new target include those acting in the extrinsic/intrinsic pathway, proteins that control the apoptosis machinery such as the p53 and proteosome pathway. Most of these forms of therapy are still in preclinical development because of their low specifity and susceptibility to drug resistance, but several of them have shown promising results. In particular, this review specifically aims at providing an update of certain molecular players that are already in use in order to target apoptosis (such as bortezomib) or which are still being clinically evaluated (such ONYX-015, survivin and exisulind/aptosyn) or which, following preclinical studies, might have the necessary requirements for becoming part of the anticancer drug programs (such as TRAIL/ Apo2L, apoptin/VP3).
Direct activation of the apoptosis machinery as a mechanism to target cancer cells
Proceedings of the National Academy of Sciences of the United States of America, 2003
Apoptosis plays a pivotal role in the cytotoxic activity of most chemotherapeutic drugs, and defects in this pathway provide a basis for drug resistance in many cancers. Thus the ability to restore apoptosis by using small molecules could have important therapeutic implications. Using a cell-free assay to simultaneously target multiple components of the apoptosis pathway, we identified a class of compounds that activate caspases in a cytochrome c-dependent manner and induce apoptosis in whole cells. By reconstituting the apoptosis pathway with purified proteins, we determined that these compounds promote the protein-protein association of Apaf-1 into the functional apoptosome. These compounds exert cytostatic and cytotoxic effects on a variety of cancer cell lines while having little or no activity against the normal cell lines tested. These findings suggest that direct activation of the basic apoptosis machinery may be a viable mechanism to selectively target cancer.
Anticancer drugs of tomorrow: apoptotic pathways as targets for drug design
Drug Discovery Today, 2003
Apoptosis or programmed cell death is a set of ordered events that enables the selective removal of cells from tissue and is essential for homeostasis and proper function of multicellular organisms. Components of this signaling network, which include ligands, such as CD95, tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand, as well as downstream molecules, such as caspases, Bcl-2 family