title: Bypassing the need for pre-sensitization of cancer cells for anticancer TRAIL therapy with secretion of novel cell penetrable form of Smac from hA-MSCs as cellular delivery vehicle.
abstract: TNF-related apoptosis inducing ligand (TRAIL) is a novel anticancer agent with selective apoptosis-inducing 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 mitochondria-derived activator of caspase (Smac) on X-linked 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 adipose-derived mesenchymal stem cells (hA-MSC-ST) could both sensitize and destroy cancerous cells. To this aim, we generated hA-MSC-ST, 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, MCF-7. 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 cells.
authors.affiliation: Department of Medical Biotechnology, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Khorashadizadeh
authors.forename: Masoud
authors.initials: M
authors.lastname: Soleimani
authors.forename: Hossein
authors.initials: H
authors.lastname: Khanahmad
authors.forename: Ali
authors.initials: A
authors.lastname: Fallah
authors.forename: Mahmood
authors.initials: M
authors.lastname: Naderi
authors.forename: Mohammadreza
authors.initials: M
authors.lastname: Khorramizadeh
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D061986:MCF-7 Cells; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000235:genetics; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human