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BMC Cancer

, 15:931

First Online: 25 November 2015Received: 03 September 2015Accepted: 19 November 2015DOI: 10.1186-s12885-015-1938-x

Cite this article as: Sahoo, S., Singh, P., Kalha, B. et al. BMC Cancer 2015 15: 931. doi:10.1186-s12885-015-1938-x

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.

KeywordsHuman chorionic gonadotropin Ectopic secretion Prognosis Chemoresistance Immunotherapy AbbreviationsERKExtracellular signal-regulated kinase

hCGHuman Chorionic Gonadotropin

HO-1Hemeoxygenase 1

IL-6Interleukin 6

TLRToll-like receptor

TNFTumor necrosis factor

Electronic supplementary materialThe online version of this article doi:10.1186-s12885-015-1938-x contains supplementary material, which is available to authorized users.

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Author: Suchismita Sahoo - Poonam Singh - Beneeta Kalha - Om Singh - Rahul Pal

Source: https://link.springer.com/







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