Programmed Cell Death in Cancer Progression and Therapy

Chemotherapeutic Approaches for Targeting Cell Death Pathways
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These observations strongly indicate that PDCD4 can induce a significant decrease in tumor cell survival and an increase in tumor apoptosis, leading to the enhanced sensitivity of CRC cells to Taxol treatment. Cell viability was examined at 48 h after treatment. Compared with the empty vector group, cell viability in the PDCD4 overexpression and Taxol treatment groups was significantly reduced, and further reduced by co-administration of Taxol and the PDCD4 plasmid.

Apoptosis was analyzed at 48 h post-treatment by flow cytometry. Compared with the empty vector group, cell apoptosis in the PDCD4 overexpression and Taxol treatment groups was significantly increased, and further induced by co-administration of Taxol and the PDCD4 plasmid. To investigate the possible mechanisms by which PDCD4 affects cell proliferation and apoptosis, PDCD4-transfected or -non-transfected cells were treated with or without Taxol, RT-qPCR and western blotting assays were then performed to detect expression of the apoptosis-associated genes Bax and Bcl-2, and the invasion-associated molecule MMP As presented in Figs.

Furthermore, treatment with Taxol resulted in the upregulation of Bax and downregulation of Bcl-2 and MMP-9 protein expression levels. At 48 h post-treatment, total cell lysates were assayed via western blotting with the indicated antibodies. GAPDH was used as the loading control.

Compared with the empty vector group, Bax protein level in the PDCD4 overexpression and Taxol treatment groups were significantly increased, which was further induced by co-administration of Taxol and the PDCD4 plasmid. Results were normalized to GAPDH and expressed relative to the empty vector group levels that were assigned a value of 1. At present, the treatment of CRC, especially advanced-stage CRC, requires neoadjuvant chemotherapy following surgical resection. With advancements in therapeutic strategies, for example, certain novel adjuvant drugs now being combined with Taxol or 5-FU, numerous patients have benefited from the chemotherapy regimens and exhibit improved overall survival.

Programmed cell death protein 1

However, this therapeutic effect is limited as disease relapse can occur from drug-resistant cells. To date, chemotherapy resistance remains one of the major causes of cancer-associated mortality among patients with CRC after therapy. Therefore, it is necessary to identify effective biomarkers to target to make CRC tumor cells more sensitive to chemotherapy drugs.

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PDCD4 was initially identified as an apoptosis-associated gene 29 and subsequently found to function as a tumor suppressor gene 30 , Further studies have shown that its loss or lower expression is strongly implicated in the progression and poor prognosis of various types of cancers including CRC 11 , Multiple regulation mechanisms have been described in association with PDCD4. Furthermore, PDCD4 can be upregulated during apoptosis in response to different inducers 29 , A growing body of evidence suggests that apoptosis is closely involved in mediating cancer cell death induced by chemotherapy drugs.

To date, and to the best of our knowledge, there have been no reports on the role of PDCD4 in the sensitivity of CRC cells to chemotherapy drugs. Taxol is one of the current chemotherapy drugs used for the treatment of CRC, but its use can result in chemoresistance and therapy failure In the present study, PDCD4 overexpression exhibited a marked inhibitory effect on proliferation and apoptosis in CRC cells treated with Taxol at the indicated concentration.

A possible mechanism underlying this effect was that PDCD4 overexpression significantly enhanced the expression of apoptosis-associated gene Bax and invasion-associated gene MMP-9, and markedly reduced the expression of the anti-apoptosis gene Bcl In addition, PDCD4 upregulation significantly elevated the sensitivity of CRC cells to the chemotherapy drug Taxol, by enhancing apoptosis and attenuating cell survival. These findings might represent a novel strategy for improving the curative effect of chemotherapy and, thus, the prognosis of patients in CRC.

DW performed the clinical and cell studies in the present study, QH and LZ also performed the clinical studies. JG performed the cell studies, and YX analyzed the data. AW designed the study and was a major contributor in writing the manuscript.


All authors read and approved the final manuscript. The ethics approval was obtained from Sanmen County People's Hospital, and written informed consent was obtained from all patients. Int J Cancer. Cancer Metastasis Rev. Fakih MG: Metastatic colorectal cancer: Current state and future directions.

J Clin Oncol. Int J Colorectal Dis. Oncol Rep. PLoS One.


I predict that combinations of BH3 mimetics with inhibitors of oncogenic kinases could be particularly promising, because the latter should only affect the cancerous, but not the healthy, cells. Since MCL-1 is critical for the survival of several essential and hard-to-replace cell types, such as cardiomyocytes, it has been argued that targeting MCL-1 will not be a viable option for cancer therapy. It is, however, important to remember that irreversible loss of a protein does not equate to transient inhibition of a protein.

Hence, targeting MCL-1 with BH3 mimetics may still be a viable strategy for cancer therapy, particularly in tumor cells exquisitely dependent on this prosurvival protein. Figure 5. Apoptosis regulators targeted for cancer therapy. If these proteins are critical for the sustained survival of these tumor cells, targeting them with BH3 mimetics may be an attractive strategy.

Since it should be possible to engineer such compounds so that they do not bind to the human BCL2-like prosurvival proteins, they would be expected to cause minimal collateral damage. Thus it might even be possible to combine them with chemotherapeutic drugs that act nonspecifically, for example, by causing DNA damage eg, cyclophosphamide, etoposide. In the case of MCL-1, which has a short half-life due in part to ubiquitin-dependent proteasomal degradation, indirect targeting might be achieved by inhibiting a deubiquitinase that delays this degradation.

Of course, since such regulators act not only upon MCL-1, but many other proteins as well, unwanted side effects may arise from effects on other client proteins. In conclusion, the first cell death regulator, BCL2, 21 and its function 35 were discovered nearly 30 and 25 years ago, respectively. Since then, the field has made enormous progress, defining the components of the cell death pathways, their functions in health and disease particularly cancer , and their structures.

This has culminated in the development of the first 2 drugs that directly flip the apoptotic switch and they are showing early promise in clinical trials for treatment of CLL and certain other cancers. Having been involved in cell death research for nearly 25 years, I hope that these drugs and future compounds will contribute to the armamentarium for treating cancer and possibly other diseases. References 1. Cell death. New Engl J Med. Apoptosis signaling. Ann Rev Biochem.


The many roles of FAS receptor signaling in the immune system. Caspase substrates. Cell Death Differ. Bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Bcldeficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Massive cell death of immature hematopoietic cells and neurons in Bcl-x deficient mice.

Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. The combined functions of proapoptotic Bcl-2 family members Bak and Bax are essential for normal development of multiple tissues. Mol Cell. Cell Death Dis. Differential targeting of pro-survival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. The role of BH3-only protein Bim extends beyond inhibiting Bcllike prosurvival proteins.

J Cell Biol. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity.

The use of the process of apoptosis for cancer treatments

Puma cooperates with Bim, the rate-limiting BH3-only protein in cell death during lymphocyte development, in apoptosis induction. J Exp Med.

CICD prompts immune system attack

Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. They conclude that tumors can remain dormant for long intervals despite constant cellular turnover and that high apoptosis rates perturb the intrinsic tumor dynamics and shift the population towards more aggressive subclones. Cell competition is a tumour suppressor mechanism in the thymus. These tumors arise as a consequence of genomic instability 97 likely provoked by repeated cycles of excessive apoptosis and subsequent proliferation during therapy. Cancer Res ; 64 : —

Death squads enlisted by the tumour suppressor p Biochem Biophys Res Commun ; : — BH3-only proteins Puma and Bim are rate-limiting for gamma-radiation- and glucocorticoid-induced apoptosis of lymphoid cells in vivo. Blood ; : — Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of pinduced apoptosis. Puma is an essential mediator of pdependent and -independent apoptotic pathways. Cancer Cell ; 4 : — Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma.

N Engl J Med ; : — Disrupted p53 function as predictor of treatment failure and poor prognosis in B- and T-cell non-Hodgkin's lymphoma.

Investigating Apoptosis, Autophagy, and Necroptosis in Neurogenerative Disease and Cancer

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Cell Death Differ e-pub ahead of print 17 October MYC oncogenes and human neoplastic disease.

How cells survive

Programmed cell death (PCD) plays pivotal roles in tumor progression, cancer therapeutics and resistance of tumor cells to therapy. With the discovery of key. Request PDF on ResearchGate | Programmed Cell Death in Cancer Progression and Therapy | Introduction Chapter 1: Cell Death: History and Future by Zahra.

Oncogene ; 18 : — Chronic lymphocytic leukemia cells display pdependent drug-induced Puma upregulation. Leukemia ; 19 : — Expression and transcriptional regulation of functionally distinct Bmf isoforms in B-chronic lymphocytic leukemia cells. Leukemia ; 18 : 41— J Clin Invest ; : — Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with In vitro and In vivo chemoresponses. Blood ; 91 : — Mimicking the tumour microenvironment: three different co-culture systems induce a similar phenotype but distinct proliferative signals in primary chronic lymphocytic leukaemia cells.

Br J Haematol ; : — Mimicking the microenvironment in chronic lymphocytic leukaemia - where does the journey go?

Programmed cell death protein 1 - Wikipedia

Llambi F, Green DR. Apoptosis and oncogenesis: give and take in the BCL-2 family. Curr Opin Genet Dev ; 21 : 12— Prednisolone resistance in childhood acute lymphoblastic leukemia: vitro-vivo correlations and cross-resistance to other drugs. Blood ; 92 : — The BCL2 rheostat in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia. Leukemia ; 22 : — CXCR4 in clinical hematology.

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Curr Top Microbiol Immunol ; : — Targeting the Bclregulated apoptosis pathway by BH3 mimetics: a breakthrough in anticancer therapy? Cell Death Differ ; 15 : — Unleashing the power of inhibitors of oncogenic kinases through BH3 mimetics. Nat Rev Cancer ; 9 : — ABT a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res ; 68 : — Cancer Res ; 72 : — Rhiner C, Moreno E. Super competition as a possible mechanism to pioneer precancerous fields. Carcinogenesis ; 30 : — Okada H, Mak TW. Pathways of apoptotic and non-apoptotic death in tumour cells.

Nat Rev Cancer ; 4 : — Ionizing radiations sustain glioblastoma cell dedifferentiation to a stem-like phenotype through survivin: possible involvement in radioresistance. Cell Death Dis ; 5 : e Cotter TG.