Abstract
Heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF) is a new promising target for the treatment of ovarian cancer. Our previous study showed that cross‐reacting material 197 (CRM197), a specific HB‐EGF inhibitor, significantly reverses resistance against paclitaxel in paclitaxel‐resistant ovarian cancer cells. However, the mechanism of the effect of CRM197 on the reversion of paclitaxel resistance was unclear. In this study, in vitro and in vivo data suggested that CRM197 treatment sensitized paclitaxel‐resistant ovarian cancer cells to paclitaxel, at least in part, via nucleus accumbens‐1 (NAC‐1) and its downstream pathway, DNA damage‐inducible 45‐γ interacting protein (Gadd45gip1)/growth arrest and DNA damage‐inducible 45 (Gadd45), in A2780/Taxol and SKOV3/Taxol cells. The results also showed that CRM197 activated the proapoptotic JNK/p38MAPK pathway to enhance caspase‐3 activity and apoptosis by downregulation of the NAC‐1/Gadd45gip1/Gadd45 pathway, leading to reversion of paclitaxel resistance in A2780/Taxol and SKOV3/Taxol cells. This study provides the first mechanism through which CRM197 significantly reverses resistance against paclitaxel by modulating the NAC‐1/Gadd45gip1/Gadd45 pathway in paclitaxel‐resistant ovarian cancer cells, and the mechanism of HB‐EGF inhibition as a novel therapeutic strategy for patients with paclitaxel‐resistant ovarian cancer.
Highlights
Ovarian cancer is the most lethal gynecological malignancy
To determine whether nucleus accumbens‐1 (NAC‐1) expression contributes to cross‐ reacting material 197 (CRM197)‐mediated reversal of paclitaxel resistance by activating the proapoptotic JNK/p38MAPK pathway, we examined cell viability and caspase‐3 activity in A2780/Taxol cells transfected with NAC‐1 shRNA (NAC‐1 shRNA1, shRNA2m and shRNA3) and RK3E cells transfected with V5‐NAC‐1 (V5‐1, V5‐2, and V5‐3)
The Gadd45gip1/Gadd45γ pathway is involved in tumor recurrence as a downstream pathway of NAC‐1.17,18 To investigate whether CRM197 reverses resistance to paclitaxel via the Gadd45gip1/Gadd45γ pathway, we examined the effect of CRM197 on the expression of Gadd45gip1/ Gadd45γ in parental (A2780 and SKOV3) and paclitaxel‐ resistant (A2780/Taxol and SKOV3/Taxol) ovarian cancer cells by western blotting
Summary
Ovarian cancer is the most lethal gynecological malignancy. Paclitaxel has been widely used as a frontline therapeutic agent for ovarian cancer.[1]. Patients who relapse or do not initially respond to traditional chemotherapy are thought to have drug‐resistant cancer cells, resulting in cancer relapse and lethality.[2] To develop a novel effective therapy to restore the chemosensitivity of patients with ovarian cancer, further understanding of the molecules and mechanisms leading to paclitaxel resistance of ovarian cancer is needed. We investigated the mechanism of CRM197 in alleviating paclitaxel resistance. We investigated the role of nucleus accumbens‐1 (NAC‐1) and its downstream pathway, growth arrest and DNA damage‐inducible 45‐γ interacting protein (Gadd45gip1)/ growth arrest and DNA damage‐inducible 45 (Gadd45), in CRM197‐mediated reversal of paclitaxel resistance in ovarian cancer cells. We further investigated regulation of the MAPK pathway by the NAC‐1/Gadd45gip1/Gadd[45] pathway following treatment of ovarian cancer cells with CRM197. We examined the effect of activation of the MAPK pathway by CRM197 on the caspase‐3 activity and cell viability
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