Abstract
Inhibitions or blockages of ligand-receptor interactions on cancer cell surfaces by exogenous competetors or antibodies often result in apoptosis or “programmed cell death.” The underlying mechanisms of action for cellular apoptosis depend greatly on the molecular nature of specific ligand-receptor interactions and the signal transduction pathways involved. Two such unrelated systems which are potentially involved in apoptosis of cancer cells are described in this review. They are, respectively, gonadotropinreleasing hormone (GnRH) receptor and cancerous immunoglobulins, or CA215, both of which are widely expressed on the surface of cancer cells from diversified tissue origins. Bindings of GnRH or its decapeptide analogs as ligands to GnRH receptor were known to induce apoptosis of several extrapituitary cell types in gonadal tissues, as well as different cancer cells. Monoclonal antibodies against the GnRH receptor of cancer cells were shown to induce apoptosis, similar to the action of GnRH analogs. In contrast, RP215 monoclonal antibody reacts specifically with the carbohydrate-associated epitope of cancerous immunoglobulins and is known to induce apoptosis of cancer cells in vitro. It also causes growth inhibition of tumor cells in nude mouse experimental models. Elucidations of the specific mechanisms of apoptosis in cancer cells of these two molecular interaction systems will not only lead to a better understanding of cancer biology but also benefit patients in cancer monitoring and therapy.
Highlights
Compared to the negative control, apoptosis induced by RP215 monoclonal antibodies (mAbs) (1 - 10 μg/mL) and goat anti-human immunoglobulin G (IgG) to cultured cancer cells were statistically significant [12,13,20]
By means of semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), the effects of RP215 mAb was analyzed through the expression of a number of genes involved in cell growth regulations of cancer cells
It was generally observed that treatments of cancer cells with RP215 mAb cause significant down-regulation of several genes responsible for protein synthesis and cell cycle control, whereas expressions of certain genes involved in the expressions of immunoglobulins such as IgG, nuclear factor kappa-B p105 subunit 1 (NFKB-1), and the cellular signal transduction activator, c-fos, are up-regulated [12]
Summary
In view of the fact that the native neuroendocrine hormones, GnRH I and GnRH II, are relatively short in circulation half-life (~minutes), GnRH analogs were synthesized and utilized as a substitute of native GnRH and demonstrated a somewhat longer half-life (~hours) in circulation These GnRH analogs were further classified as agonists and antagonists, depending on their hormone actions in the pituitary gland [5,6]. GnRH receptor, especially those specific to the extracellular domain of N1-29 synthetic peptide, have been successfully generated and characterized [10,11] These mAbs can be considered as long acting and high molecular weight GnRH analogs with an average half-life of 5 - 21 days in circulation. Our aim is to evaluate if GHR106 mAb can be a suitable substitute for GnRH agonists and can be used as a long-acting anticancer drug, following humanization and clinical studies [13]
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