Abstract
BackgroundHuman chorionic gonadotropin (hCG) has essential roles in pregnancy. Reports linking hCG in non-trophoblastic tumors with poor patient prognosis has spurred interest in patho-physiological roles the hormone might play.MethodsThe ability of hCG to prevent tumor cell death and sustain viability in the presence of chemotherapeutic drugs was assessed and potential synergies with TLR ligands explored. hCG-induced up-modulation of genes involved in chemoresistance was documented and targets validated by siRNA knock-down. Whether hCG could drive collaboration between tumor cells and macrophages in the production of IL-6 and consequent chemoresistance was assessed. The effects of concurrent anti-hCG immunization and chemotherapy on the growth of syngeneic murine tumors were evaluated.ResultshCG maintained basal levels of cytokine secretion by tumor cells exposed to chemotherapeutic drugs, and enhanced viability and proliferation; pre-treatment with hCG also decreased apoptosis, as assessed by Annexin-V binding and the cleavage of caspase 3. While co-incubation with hCG along with several TLR ligands mediated heightened chemo-resistance, TLR-2/6 and TLR-9 ligands increased the phosphorylation of JNK, and TLR-2 and TLR-8 ligands the phosphorylation of ERK in presence of hCG and curcumin, providing evidence of tri-molecular synergy. The hormone increased the transcription and/or expression of molecular intermediates (SURVIVIN, HIF-1α, PARP-1, Bcl-2, c-FLIP, KLK-10, XIAP, c-IAP-1) associated with chemo-resistance and increased levels of stress modulators (PON2, HO-1, HSP27 and NRF-2). siRNAs to SURVIVIN, NRF-2, HO-1 and HIF-1α attenuated hCG-mediated chemo-resistance. hCG-conditioned tumor cell supernatants induced heightened secretion of IL-6 and TNF-α from peripheral blood adherent cells and secreted IL-6 imparted chemo-resistance to naïve tumor cells. Co-administration of curcumin along with an anti-hCG vaccine (hCGβ conjugated to Tetanus Toxoid (TT)) to mice carrying syngeneic tumors resulted in significantly enhanced benefits on animal survival; synergy was demonstrated between anti-hCG antibodies and curcumin in the reduction of tumor cell viability.ConclusionsThe data suggest that hCG, via direct as well as collaborative effects with TLR ligands and accessory cell-secreted cytokines, mediates chemo-resistance in gonadotropin-sensitive tumors and outlines the potential benefits of combination therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1938-x) contains supplementary material, which is available to authorized users.
Highlights
Human chorionic gonadotropin has essential roles in pregnancy
Effects of Human chorionic gonadotropin (hCG) on chemotherapeutic drug-induced loss of tumor cell viability Based on the association of hCG with increased chemoresistance [9,20], whether hCG can directly induce chemo-resistance in tumor cells was ascertained. hCG pre-exposure resulted in a significant reduction in druginduced decrease in viability in both human and murine tumor cells, though individual responses varied (Fig. 1c); while hCG protected COLO-205 cells from only low to Effects of hCG on chemotherapeutic drug-induced apoptosis of tumor cells Drug resistance is a multifactorial process and is characterized by dysregulation of the equilibrium between cell survival and apoptosis [21]
Though the increase in the viability and proliferation of tumor cells upon exposure to exogenous hCG in this study are in line with similar findings by previous investigators, the molecular mechanisms linking the hormone to chemo-resistance have not been investigated in any detail, save for a study demonstrating the ability of hCG to induce resistance to cisplatin in ovarian cancer cells [30]
Summary
Reports linking hCG in non-trophoblastic tumors with poor patient prognosis has spurred interest in patho-physiological roles the hormone might play. A glycoprotein hormone specific to primates, is possibly the first maternal indicator of pregnancy. It extends the life of the corpus luteum to elicit the continued secretion of progesterone [1], enables implantation and trophoblast invasion, and supports angiogenesis [2, 3]. Several non-trophoblastic tumors have been shown to express human chorionic gonadotropin (hCG) or its constituent subunits [4,5,6]. Incubation of bladder cancer cells with hCGβ leads to dose-dependent proliferation [7], and tumor-derived hCG is associated with unresponsiveness to treatment and decreased survival [8, 9]. Evidence for a pro-tumorigenic role for hCG has been provided by transgenic models; mice expressing hCG develop gonadal neoplasia and extra-gonadal tumors [12]
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