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Targeting Neural-Restrictive Silencer Factor Sensitizes Tumor Cells to Antibody-Based Cancer Immunotherapy In Vitro via Multiple Mechanisms
- Source :
- The Journal of Immunology. 184:6035-6042
- Publication Year :
- 2010
- Publisher :
- The American Association of Immunologists, 2010.
-
Abstract
- Tumor cells escape clearance by complement by abundantly expressing CD59 and other membrane complement regulators. Recently, we designed a peptide derived from the neural-restrictive silencer factor (REST), REST68, which we showed to inhibit expression of CD59 in tumors lacking the full-length REST and proposed a detailed model for regulation of CD59 expression via interplay between REST and nucleolin (NCL) transcription factors. In this paper, we study in detail the mechanisms for sensitization of malignant cells to Ab-based cancer immunotherapy by the REST68 peptide and the implications of the REST/NCL model for the design of treatment resulting in higher tumor susceptibility. REST68 inhibited CD59 expression in malignant cells expressing either truncated or full-length REST, but not in nonmalignant cells. However, activation of protein kinase C (PKC) in nonmalignant cells, a process that contributes to cellular transformation, phosphorylated NCL and enabled suppression of CD59 expression by the REST68. Combined treatment of different tumor types with REST68 and PKC inhibitor synergized to further suppress CD59 expression and reduce resistance to complement lysis. The combined treatment also increased susceptibility of tumors expressing either of the REST isoforms to PBMC-mediated killing, which, at least in part, accounted for the strong promotion of apoptosis by the REST68/PKC inhibitor. These data demonstrate that REST68 sensitizes tumors to Ab-based cancer immunotherapy via multiple mechanisms. Furthermore, the REST/NCL interplay model for regulation of expression of cd59 and other genes involved in cell survival enables the design of treatments for different tumor types to achieve more efficient tumor clearance.
- Subjects :
- Cytotoxicity, Immunologic
medicine.medical_treatment
Blotting, Western
Immunology
Gene Expression
Antineoplastic Agents
Apoptosis
CD59 Antigens
chemical and pharmacologic phenomena
Cell Separation
CD59
In Vitro Techniques
Cancer immunotherapy
Cell Line, Tumor
Neoplasms
Gene expression
medicine
Humans
Immunology and Allergy
Transcription factor
Protein kinase C
biology
Antibodies, Monoclonal
RNA-Binding Proteins
Flow Cytometry
Phosphoproteins
Repressor Proteins
Cell culture
Cancer research
biology.protein
Immunotherapy
Antibody
Nucleolin
Subjects
Details
- ISSN :
- 15506606 and 00221767
- Volume :
- 184
- Database :
- OpenAIRE
- Journal :
- The Journal of Immunology
- Accession number :
- edsair.doi.dedup.....cb7d7989df8b4d50785075fb5848ffbf