scholarly journals Deciphering the Mechanism of Action Involved in Enhanced Suicide Gene Colon Cancer Cell Killer Effect Mediated by Gef and Apoptin

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 264 ◽  
Author(s):  
Blanca Cáceres ◽  
Alberto Ramirez ◽  
Esmeralda Carrillo ◽  
Gema Jimenez ◽  
Carmen Griñán-Lisón ◽  
...  

Despite the great advances in cancer treatment, colorectal cancer has emerged as the second highest cause of death from cancer worldwide. For this type of tumor, the use of suicide gene therapy could represent a novel therapy. We recently demonstrated that co-expression of gef and apoptin dramatically inhibits proliferation of the DLD-1 colon cell line. In the present manuscript, we try to establish the mechanism underlying the enhanced induction of apoptosis by triggering both gef and apoptin expression in colon tumor cells. Scanning microscopy reveals that simultaneous expression of gef and apoptin induces the apparition of many “pores” in the cytoplasmic membrane not detected in control cell lines. The formation of pores induced by the gef gene and accentuated by apoptin results in cell death by necrosis. Moreover, we observed the presence of apoptotic cells. Performing protein expression analysis using western blot, we revealed an activation of mitochondrial apoptosis (increased expression of Pp53, cytochrome c, Bax, and caspase 9) and also the involvement of the extrinsic pathway through caspase 8activation. In conclusion, in this manuscript we demonstrate for the first time that the extrinsic pathway of apoptosis and pore formation is also involved in the cell death caused by the co-expression of the gef and apoptin genes. Our results suggest that co-expression of gef and apoptin genes induces an increase in post-apoptotic necrotic cell death and could be a valuable tool in the design of new antitumor strategies focused on the enhancement of the immune response against cancer cell death.

Author(s):  
Amanda S. Coutts ◽  
Sandra Maniam ◽  
Nicholas B. La Thangue

Inducing cancer cell death is the basis of the majority of cancer treatments and understanding the mechanisms that control cell death is of prime clinical importance. As a defining feature of cancer is the ability to circumvent cell death pathways, understanding the mechanisms involved is also important in the development of novel therapeutic agents. This chapter outlines three main mechanisms involved in cancer cell death—apoptosis, necroptosis, and autophagy—to give an overview of some of the specific pathways involved. There are a plethora of genetic and epigenetic changes in tumour cells that can circumvent apoptotic pathways; as such understanding and developing therapies that can target other death-signalling pathways could have great clinical significance. Given the complexity involved in the variety of cell death mechanisms, the challenge in oncology is how to harness these different modes of cell death in order to effectively eliminate cancer cells.


2016 ◽  
Vol 23 (15) ◽  
pp. 1513-1527 ◽  
Author(s):  
Magdalena Gorska ◽  
Alicja Kuban-Jankowska ◽  
Jaroslaw Slawek ◽  
Michal Wozniak

2019 ◽  
Vol 234 (11) ◽  
pp. 20648-20661 ◽  
Author(s):  
Zhen Yu ◽  
Ze Yu ◽  
ZhenBao Chen ◽  
Lin Yang ◽  
MingJun Ma ◽  
...  

2021 ◽  
Author(s):  
Wooram Park ◽  
Seok-Jo Kim ◽  
Paul Cheresh ◽  
Jeanho Yun ◽  
Byeongdu Lee ◽  
...  

Mitochondria are crucial regulators of the intrinsic pathway of cancer cell death. The high sensitivity of cancer cells to mitochondrial dysfunction offers opportunities for emerging targets in cancer therapy. Herein,...


2013 ◽  
Vol 24 (8) ◽  
pp. 1414-1414 ◽  
Author(s):  
Megan A. Mackey ◽  
Farhat Saira ◽  
Mahmoud A. Mahmoud ◽  
Mostafa A. El-Sayed

Nanomaterials ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 2003
Author(s):  
Samet Kocabey ◽  
Aslihan Ekim Kocabey ◽  
Roger Schneiter ◽  
Curzio Rüegg

DNA nanotechnology offers to build nanoscale structures with defined chemistries to precisely position biomolecules or drugs for selective cell targeting and drug delivery. Owing to the negatively charged nature of DNA, for delivery purposes, DNA is frequently conjugated with hydrophobic moieties, positively charged polymers/peptides and cell surface receptor-recognizing molecules or antibodies. Here, we designed and assembled cholesterol-modified DNA nanotubes to interact with cancer cells and conjugated them with cytochrome c to induce cancer cell apoptosis. By flow cytometry and confocal microscopy, we observed that DNA nanotubes efficiently bound to the plasma membrane as a function of the number of conjugated cholesterol moieties. The complex was taken up by the cells and localized to the endosomal compartment. Cholesterol-modified DNA nanotubes, but not unmodified ones, increased membrane permeability, caspase activation and cell death. Irreversible inhibition of caspase activity with a caspase inhibitor, however, only partially prevented cell death. Cytochrome c-conjugated DNA nanotubes were also efficiently taken up but did not increase the rate of cell death. These results demonstrate that cholesterol-modified DNA nanotubes induce cancer cell death associated with increased cell membrane permeability and are only partially dependent on caspase activity, consistent with a combined form of apoptotic and necrotic cell death. DNA nanotubes may be further developed as primary cytotoxic agents, or drug delivery vehicles, through cholesterol-mediated cellular membrane interactions and uptake.


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