Lunasin and Cancer

Lunasin is a naturally existing bioactive peptide with an Arg-Gly-Asp (RGD) motif, which competes with integrins to bind with the extracellular matrix (ECM) consequently suppressing the integrin-mediated signaling pathway. Owing to the RGD motif, lunasin has been proven as an effective anti-inflammatory, antitumor and antimetastatic agent in many types of cancer. However, knowledge of its inhibitory effect on metastasis and the related mechanism of action in breast cancer cells is limited. In this study, the inhibitory effect of lunasin on the proliferation, migration and invasion of two typical breast cancer cell lines, ER-negative MDA-MB-231 with αVβ3 expression and ER-positive MCF-7 with αVβ5/α5β1 expression, were examined in vitro as well the related mechanisms. The results demonstrated that lunasin (10-20 µM) effectively inhibited the migration and invasion activity and expression of matrix metalloproteinase (MMP)”‘2/-9 in both breast cancer cell lines. Meanwhile, we also found that lunasin inhibited the phosphorylation of focal adhesion kinase (FAK), Src, Akt, ERK and nucleus translocation of NF-κB, which indicates that, possibly via competing with αVβ3 or αVβ5/α5β1 integrin, lunasin suppresses the metastasis of breast cancer cells through integrin-mediated FAK/Akt/ERK and NF-κB signaling pathways followed by downregulation of the activity and expression of MMP-2/-9.

Immune modulating functions by soypeptide lunasin in cancer immunotherapy

Chun-Yu Tung, Purdue University

http://docs.lib.purdue.edu/dissertations/AAI10151561/

Abstract

Chemotherapy is currently the mainstay of treatment for most cancer patients. Despite its efficacy in eliminating cancer cells, a high percentage of chemotherapy patients eventually relapse or suffer progression of the disease. Immunosurveillance is capable of recognizing and eliminating continuously arising transformed mutant cells, and thus cancer immunotherapy is one of the emerging therapeutic strategies that harnesses the power of the immune system to eradicate chemotherapy-resistant cancerous cells. However, the adverse side effects of chemotherapy impede the therapeutic effects of immunotherapy.

Our previous studies demonstrate that lymphoma patients are refractory to clinical immunotherapy because of chemotherapy-induced immune dysfunction. In addition, tumors can induce immune suppression, which allows them to escape immunosurveillance. Thus, it is prudent to develop an efficacious immunotherapy that would enhance anti-tumor immunity in cancer patients who are most often immunodeficient. ^ Lunasin, a 43-amino acid peptide, was originally isolated from soybeans. The current study discovered a novel function of lunasin as a vaccine adjuvant, which enhanced the development of protective immune responses to soluble vaccine antigens. It was found that lunasin-treated conventional DCs (cDCs) not only expressed elevated levels of co-stimulatory molecules (CD86, CD40) but also exhibited up-regulation of cytokines (IL1B, IL6) and chemokines (CCL3, CCL4). Lunasin-treated cDCs induced higher proliferation of allogeneic CD4+ T cells when compared with a medium-only control in the mixed leukocyte reaction (MLR). In addition, lunasin enhanced cross-presentation of soluble antigens by mouse CD11c+DCs and CD8α+DCs, resulting in effective priming of antigen-specific IFNγ producing CD8+ T cells. Immunization with etoposide-treated B-lymphoma cells and lunasin provided nearly 100% protection against tumor growth. Furthermore, inclusion of lunasin in the cancer vaccine model prevented tumor relapse after chemotherapy. ^ The immunomodulatory function of lunasin has also been identified in the STAT4 deficiency model.

Our previous studies demonstrated that lymphoma patients were refractory to IL-12-based immunotherapy because of chemotherapy-induced immune dysfunctions associated with acquired deficiency of STAT4. To directly determine the requirement for STAT4 in response to lunasin-based cancer vaccination, a syngeneic B-lymphoma in a prophylactic model was utilized to compare the inhibition of tumor growth in wild-type BALB/c (WT) mice versus STAT4 deficient (Stat4^-/-) mice. B-lymphoma cells subcutaneously implanted into Stat4^-/- mice have similar tumor growth and progression when compared to WT mice. Lunasin-based whole tumor vaccination induces the development of tumor-specific CD4+ and CD8+ T cells in WT and Stat4^-/- mice. In conclusion, Stat4^-/- mice do not exhibit accelerated subcutaneous tumor growth over WT mice following lunasin-based vaccination in a syngeneic B-lymphoma model. ^ Collectively, these studies provide the evidence for lunasin as an immunomodulatory agent that enhances the cross-presentation activity of DCs and promotes antigen-specific antitumor immune responses in cancer immunotherapy.^