Targeting progastrin enhances radiosensitization of colorectal cancer cells
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Aline Kowalski-Chauvel1, Valerie Gouaze-Andersson1, Alix Vignolle-Vidoni1, Caroline Delmas1,2, Christine Toulas1,2, Elizabeth Cohen-Jonathan-Moyal1,2 and Catherine Seva1
1Cancer Research Center of Toulouse (CRCT), UMR1037 Inserm/University Toulouse III Paul Sabatier, Toulouse, France
2IUCT Oncopole, Toulouse, France
Catherine Seva, email: firstname.lastname@example.org
Keywords: colorectal cancer, radioresistance, progastrin, cell signalling, ionizing radiations
Abbreviations: CRC, colorectal cancer; PG, progastrin; IR, ionizing radiations; PARP-1, poly-(ADP-ribose)-polymerase-1; DSBs, double-strand breaks
Received: January 04, 2017 Accepted: March 20, 2017 Published: April 20, 2017
A high percentage of advanced rectal cancers are resistant to radiation. Therefore, increasing the efficacy of radiotherapy by targeting factors involved in radioresistance seems to be an attractive strategy. Here we demonstrated that the pro-hormone progastrin (PG), known to be over-expressed in CRC, and recognized as a pro-oncogenic factor, is a radioresistance factor that can be targeted to sensitize resistant rectal cancers to radiations. First, we observed an increase in PG mRNA expression under irradiation. Our results also demonstrated that down-regulating PG mRNA expression using a shRNA strategy, significantly increases the sensitivity to irradiation (IR) in a clonogenic assay of different colorectal cancer cell lines. We also showed that the combination of PG gene down-regulation and IR strongly inhibits tumours progression in vivo. Then, we demonstrated that targeting PG gene radiosensitizes cancer cells by increasing radio-induced apoptosis shown by an increase in annexin V positive cells, caspases activation and PARP cleavage. We also observed the up-regulation of the pro-apoptotic pathway, JNK and the induction of the expression of pro-apoptotic factors such as BIM. In addition, we demonstrated in this study that inhibition of PG gene expression enhances radiation-induced DNA damage. Our data also suggest that, in addition to increase radio-induced apoptosis, targeting PG gene also leads to the inhibition of the survival pathways, AKT and ERK induced by IR.
Taken together, our results highlight the role of PG in radioresistance and provide a preclinical proof of concept that PG represents an attractive target for sensitizing resistant rectal tumours to irradiation.
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