Tae Woo Kim

6-Shogaol Overcomes Gefitinib Resistance via ER Stress in Ovarian Cancer Cells

In women, ovary cancer is already the fifth leading cause of mortality worldwide. The use of cancer therapies, such as surgery, radiotherapy, and chemotherapy, may be a powerful anti-cancer therapeutic strategy; however, these therapies still have many problems, including resistance, toxicity, and side effects. Therefore, natural herbal medicine has the potential to be used for cancer therapy because of its low toxicity, fewer side effects, and high success. This study aimed to investigate the anti-cancer effect of 6-shogaol in ovarian cancer cells. 6-shogaol induces ER stress and cell death via the reduction in cell viability, the increase in LDH cytotoxicity, caspase-3 activity, and Ca2+ release, and the upregulation of GRP78, p-PERK, p-eIF2α, ATF-4, CHOP, and DR5. Moreover, 6-shogaol treatment medicates endoplasmic reticulum (ER) stress and cell death by upregulating Nox4 and releasing ROS. The knockdown of Nox4 in ovarian cancer cells inhibits ER stress and cell death by blocking the reduction in cell viability and the enhancement of LDH cytotoxicity, caspase-3 activity, Ca2+, and ROS release. In gefitinib-resistant ovarian cancer cells, A2780R and OVCAR-3R, 6-shogaol/gefitinib overcomes gefitinib resistance by inhibiting EMT phenomena such as the reduction in E-cadherin, and the increase in N-cadherin, vimentin, Slug, and Snail. Therefore, our results suggest that 6-shogaol exerts a potential anti-cancer effect in ovarian cancer and combination treatment with 6-shogaol and gefitinib may provide a novel anti-tumor therapeutic strategy in gefitinib-resistant ovarian cancer.

JI017, a Complex Herbal Medication, Induces Apoptosis via the Nox4–PERK–CHOP Axis in Ovarian Cancer Cells

Many anti-cancer drugs, including paclitaxel and etoposide, have originated and been developed from natural products, and traditional herbal medicines have fewer adverse effects and lesser toxicity than anti-tumor reagents. Therefore, we developed a novel complex herbal medicine, JI017, which mediates endoplasmic reticulum (ER) stress and apoptosis through the Nox4–PERK–CHOP signaling pathway in ovarian cancer cells. JI017 treatment increases the expression of GRP78, ATF4, and CHOP and the phosphorylation of PERK and eIF2α via the upregulation of Nox4. Furthermore, it increases the release of intracellular reactive oxygen species (ROS), the production of intracellular Ca2+, and the activation of exosomal GRP78 and cell lysate GRP78. Combination treatment using the sarco/endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin (TG) and JI017 reportedly induces increased ER stress and cell death in comparison to the control; however, knockdown experiments of PERK and CHOP indicated suppressed apoptosis and ER stress in JI017-treated ovarian cancer cells. Furthermore, targeting Nox4 using specific siRNA and pharmacological ROS inhibitors, including N-acetylcystein and diphenylene iodonium, blocked apoptosis and ER stress in JI017-treated ovarian cancer cells. In the radioresistant ovarian cancer model, when compared to JI017 alone, JI017 co-treatment with radiation induced greater cell death and resulted in overcoming radioresistance by inhibiting epithelial–mesenchymal-transition-related phenomena such as the reduction of E-cadherin and the increase of N-cadherin, vimentin, Slug, and Snail. These findings suggest that JI017 is a powerful anti-cancer drug for ovarian cancer treatment and that its combination treatment with radiation may be a novel therapeutic strategy for radioresistant ovarian cancer.