Authors: Mohsen Khorashadizadeh Masoud Soleimani Hossein Khanahmad Ali Fallah Mahmood Naderi Mohammadreza Khorramizadeh
Publish Date: 2015/01/15
Volume: 36, Issue: 6, Pages: 4213-4221
Abstract
TNFrelated apoptosis inducing ligand TRAIL is a novel anticancer agent with selective apoptosisinducing activity on cancer cells However many malignant tumors still remain unresponsive Although cells can bypass apoptosis by different functions the defect in the blocking role of second mitochondriaderived activator of caspase Smac on Xlinked inhibitor of apoptosis protein XIAP is known to be an important hub for immortal characteristic of malignant cells Actually XIAP is known as an apoptosis inhibitor To date the sensitization of cancerous cells to TRAIL was successfully performed with different protocols mainly through blocking XIAP with Smac administration However all these sensitization methodologies need to be performed prior to TRAIL administration on cancerous cells which in turn limit their practical application in clinics Therefore we hypothesized that concurrent expression of Smac and TRAIL on human adiposederived mesenchymal stem cells hAMSCST could both sensitize and destroy cancerous cells To this aim we generated hAMSCST secreting a novel cell penetrable form of Smac and a trimeric form of TRAIL Indeed the cell penetrable form of Smac obviates the need for any pretreatment of cancerous cells Our data depicted that individual overexpression of TRAIL or Smac in different breast cancer cell types induced limited or no apoptosis respectively Conversely their concomitant overexpression markedly increased cell death even for a resistant type of breast cancer cells MCF7 Notably we observed no cytotoxicity of our methodology on normal cells In summary this is the first demonstration that a dual approach using simultaneous overexpression of a cell penetrable form of Smac and TRAIL sensitize and promote apoptotic process even in resistant breast cancer cellsThis work was funded by the Tehran University of Medical Sciences Tehran Iran The authors appreciate Stem Cell Technology Research Center Tehran Iran for providing technical support The authors are grateful to Mr Majid Mosahebi for providing human fibroblast cells Moreover I would like to specially thank Dr Haghpanah for his scientific comments during the writing of this manuscript
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