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Cancers 2019, 11(2), 264; https://doi.org/10.3390/cancers11020264

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

1
Motril Health Center, Hospital Santa Ana, Motril, 18600 Granada, Spain
2
Biopathology and Medicine Regenerative Institute (IBIMER), University of Granada, 18016 Granada, Spain
3
Biosanitary Institute of Granada (ibs. GRANADA), SAS-Universidad de Granada, 18016 Granada, Spain
4
Department of Human Anatomy and Embryology, University of Granada, 18016 Granada, Spain
5
Research Unit “Modeling Nature” (MNat), University of Granada, 18016 Granada, Spain
6
Department of Health Sciences, University of Jaén, E-23071 Jaén, Spain
*
Author to whom correspondence should be addressed.
Received: 6 December 2018 / Revised: 20 February 2019 / Accepted: 20 February 2019 / Published: 23 February 2019
(This article belongs to the Special Issue Colorectal Cancers)
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PDF [2138 KB, uploaded 23 February 2019]
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Abstract

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. View Full-Text
Keywords: gef gene; apoptin gene; combined therapy; apoptosis; caspase 3; caspase 8; caspase 9; necrosis; pore gef gene; apoptin gene; combined therapy; apoptosis; caspase 3; caspase 8; caspase 9; necrosis; pore
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Cáceres, B.; Ramirez, A.; Carrillo, E.; Jimenez, G.; Griñán-Lisón, C.; López-Ruiz, E.; Jiménez-Martínez, Y.; Marchal, J.A.; Boulaiz, H. Deciphering the Mechanism of Action Involved in Enhanced Suicide Gene Colon Cancer Cell Killer Effect Mediated by Gef and Apoptin. Cancers 2019, 11, 264.

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