Gonadotropin-mediated tumour cell chemoresistance: Evidence for multiple pathways, LH antagonism, TLR agonist and apoptotic bleb additivity, and exosome-mediated horizontal transfer

Abstract

Abstract Background Human chorionic gonadotropin (hCG), critical to the success of pregnancy, is also made by many cancers. The presence of tumour-derived hCG (or its β subunit) is associated with poor patient prognosis, the reasons for which remain largely obscure; similar links with the closely-related gonadotropins luteinizing hormone (LH) or follicle stimulating hormone (FSH) have not been described. This study was prompted by the fact that chemoresistance is associated with poor patient prognosis in a variety of cancers. Methods The ability of αhCG, βhCG, hCG, LH and FSH to protect tumor cells (of three different lineages) from the detrimental effects of six different cytotoxic drugs (in terms of viability, proliferation, and apoptosis) was assessed, and potential LH-mediated antagonisms on hCG- and βhCG-mediated chemoprotection evaluated; associated signalling events were delineated employing phosphoblots and inhibitors. Potential TLR agonist- and apoptotic bleb-additivity in chemoprotection was determined. The ability of hormone-induced, tumor cell-elicited exosomes to horizontally transfer chemoprotection to gonadotropin-naïve tumor cells was assessed. The unpaired Student’s t-test, or one-way ANOVA (Holm-Sidak) were used to calculate statistical significance. Results hCG as well as its β subunit (but its α subunit, nor LH or FSH) significantly reduced the viability-decreasing, anti-proliferative and apoptosis-inducing effects of six chemotherapeutic drugs, and of UV radiation, on the tumour cells of three distinct lineages; LH and (but not FSH) antagonised the chemo-protective action of hCG and βhCG, a finding indicative of overlapping binding sites but differential signalling. Indeed, hCG and βhCG triggered signalling pathways that were distinct from those triggered by LH and FSH in tumor cells, and specific signalling pathways drove hCG-mediated chemoprotection against specific drugs. Co-incubation of hCG with agonists for TLR-7, TLR-8, TLR-9, or with specific apoptotic blebs (components of which include endogenous TLR agonists), resulted in additive amelioration of drug action. Further, hCG-elicited (but not LH- or FSH-elicited) tumour exosomes mediated the horizontal transfer of chemoresistance to gonadotropin-naïve tumor cells. Conclusion Anti-hCG immunization (already demonstrated to have anti-tumor effects) coupled with specific drug-signalling inhibitor combinations, and/or LH supplementation, could be beneficial in subjects harbouring gonadotropin-responsive tumours.