Genistein Sensitizes Human Cholangiocarcinoma Cell Lines to Be Susceptible to Natural Killer Cells

Abstract

Cholangiocarcinoma (CCA) is a lethal bile duct cancer, which has poor treatment outcomes due to its high resistance to chemotherapy and cancer recurrence. Activation of aberrant anti-apoptotic signaling pathway has been reported to be a mechanism of chemoresistance and immune escape of CCA. Therefore, reversal of anti-apoptotic signaling pathway represents a feasible approach to potentiate effective treatments, especially for CCA with high chemoresistance. In this study, we demonstrated the effects of genistein on reactivation of apoptosis cascade and increase the susceptibility of CCA cells to natural killer (NK-92) cells. Genistein at 50 and 100 µM significantly activated extrinsic apoptotic pathway in CCA cells (KKU055, KKU100, and KKU213A), which was evident by reduction of procaspase-8 and -3 expression. Pretreatment of CCA cells with genistein at 50 µM, but not NK-92 cells, significantly increased NK-92 cell killing ability over the untreated control, suggesting the ability of genistein to sensitize CCA cells. Interestingly, genistein treatment could greatly lower the expression of cFLIP, an anti-apoptotic protein involved in the immune escape pathway, in addition to upregulation of death receptors, Fas- and TRAIL-receptors, in CCA cells, which might be the underlying molecular mechanism of genistein to sensitize CCA to be susceptible to NK-92 cells. Taken together, this finding revealed the benefit of genistein as a sensitizer to enhance the efficiency of NK cell immunotherapy for CCA.

Focusing on the Immune Cells: Recent Advances in Immunotherapy for Biliary Tract Cancer

“… 108 , 109 Genistein, an isoflavone derived from soybean products, is well documented for its anti-tumor effect, similarly upregulating DR4 and DR5 expression on iCCA cells. 110 …”

Heterogeneity of Cholangiocarcinoma Immune Biology

“…Likewise, sensitizing CCA cells to immune cell cytotoxic activity with the aim of enhancing the immune system activation has also shown promising results and could be considered an alternative strategy. As an example, both cordycepin [ 86 ] and genistein [ 87 ] have been shown to effectively sensitize CCA cells to NK cytotoxicity, supporting their use as alternative immunomodulating agents in CCA.…”