engleski

Integrin α Vβ 3 : link between resistance to cisplatin and adenovirus transduction efficacy

Adenoviral gene therapy is an approach for treating cancers resistant to currently available therapies, for example drug resistant cells that appear often after chemotherapy. Adenovirus infection occurs via direct binding of the fiber knob domain to CAR (coxsackie and adenovirus receptor), followed by receptor mediated endocytosis of the virion through interaction of penton base Arg-Gly-Asp (RGD) motifs with cellular integrins α vβ 3, α vβ 5, α vβ 1 and α 5β 1 and α 3β 1. We found increased expression of α vβ 3 integrin and CAR in human laryngeal carcinoma (HEp2)-derived cell line resistant to cisplatin. This led to the 5-fold increased adenovirus transduction efficacy. On the model of α vβ 3 integrin and CAR stable transfectants we showed the parallelism between α vβ 3 integrin/CAR expressions and adenovirus transduction. We showed the causative relationship between expression of α vβ 3 integrin and resistance to cisplatin, doxorubicin and mitomycine C. In HEp2-α vβ 3 expressing cells we revealed the mechanism of resistance that is glutathione-dependent elimination of drug induced ROS. On the model of tongue squamous carcinoma cells (Cal27), which express a small amount of α vβ 3 integrin, we investigated whether similar mechanism exists in a different cell model. Our results showed that both Cal27-derived α vβ 3 integrin expressing cell lines, in comparison to Cal27 cells, were resistant to cis-diamminedichloroplatinum (cisplatin), doxorubicin and mitomycine C. Conversely, increasing CAR expression in HEp2 cells (HEp2-CAR transfectants) didn’ t confer resistance to any of the tested drugs. In order to monitor modulation of CAR and integrin expressions during cisplatin treatment we treated HEp2 cells with very small amounts of cisplatin that do not induce apoptosis and observed upregulation of CAR and α vβ 5 integrin in HEp2 cells, while we didn’ t observe the de novo expression of α vβ 3 integrin. However the cisplatin treatment in both human rhabdomiosarcoma as well as in human embryonal kidney cell lines, led to the upregulation of all three molecules: CAR, α vβ 5 and α vβ 3 integrins. Our findings could have clinical importance because tumor cells that became resistant due to the α vβ 3 integrin upregulation could be a better target for adenovirus gene therapy than the parental tumor ; i.e. a lower dose of adenovirus could achieve the same therapeutic outcome as a higher dose. In addition, our results implicate that even small doses of cisplatin significantly modulate the expression of adenovirus receptors and therefore could be used as adjuvant to increase adenovirus transduction efficacy.

integrin α Vβ 3; cisplatin; resistance; adenovirus; transduction

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