title: Gonadotropin-mediated chemoresistance: Delineation of molecular pathways and targets.
abstract: BACKGROUND
  Human 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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  hCG 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Immunoendocrinology Lab, National Institute of Immunology, Aruna Asaf Ali Marg, JNU Complex, New Delhi, Delhi-110067, India. roshni413@gmail.com.
authors.forename: Suchismita
authors.initials: S
authors.lastname: Sahoo
authors.affiliation: Immunoendocrinology Lab, National Institute of Immunology, Aruna Asaf Ali Marg, JNU Complex, New Delhi, Delhi-110067, India. poonamparihaar205@nii.ac.in.
authors.forename: Poonam
authors.initials: P
authors.lastname: Singh
authors.affiliation: Immunoendocrinology Lab, National Institute of Immunology, Aruna Asaf Ali Marg, JNU Complex, New Delhi, Delhi-110067, India. beneetakalha@nii.ac.in.
authors.forename: Beneeta
authors.initials: B
authors.lastname: Kalha
authors.affiliation: Immunoendocrinology Lab, National Institute of Immunology, Aruna Asaf Ali Marg, JNU Complex, New Delhi, Delhi-110067, India. omsingh@gmail.com.
authors.forename: Om
authors.initials: O
authors.lastname: Singh
authors.affiliation: Immunoendocrinology Lab, National Institute of Immunology, Aruna Asaf Ali Marg, JNU Complex, New Delhi, Delhi-110067, India. rahul@nii.ac.in.
authors.forename: Rahul
authors.initials: R
authors.lastname: Pal
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D006063:Chorionic Gonadotropin / Q000378:metabolism* / Q000494:pharmacology; D018920:Coculture Techniques; D003474:Curcumin / Q000008:administration & dosage / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D019496:Cancer Vaccines; D006063:Chorionic Gonadotropin; C508600:IL6 protein, human; D015850:Interleukin-6; D051193:Toll-Like Receptors; D003474:Curcumin