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.
Highlights
Targeting Neural-Restrictive Silencer Factor Sensitizes Tumor Cells to Antibody-Based Cancer Immunotherapy In Vitro via Multiple Mechanisms
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 restrictive silencer factor (REST)/NCL model for the design of treatment resulting in higher tumor susceptibility
This REST/NCL model implies that protein kinase inhibitors, which have become increasingly popular for the treatment of different malignancies, will be inefficient suppressors of genes regulated by REST/NCL interplay, in tumors that lack full-length REST
Summary
Targeting Neural-Restrictive Silencer Factor Sensitizes Tumor Cells to Antibody-Based Cancer Immunotherapy In Vitro via Multiple Mechanisms. MCReg-blocking experiments showed that the increased sensitization to complement attack by the GF was entirely a consequence of the inhibited expression of the mCReg. REST68 and GF treatments sensitize tumor cells to killing by PBMCs
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
