Inhibition of Phospho-S6 Kinase, a Protein Involved in the Compensatory Adaptive Response, Increases the Efficacy of Paclitaxel in Reducing the Viability of Matrix-Attached Ovarian Cancer Cells

Abstract

ObjectiveTo identify the proteins involved the compensatory adaptive response to paclitaxel in ovarian cancer cells and to determine whether inhibition of the compensatory adaptive response increases the efficacy of paclitaxel in decreasing the viability of cancer cells.MethodsWe used a reverse-phase protein array and western blot analysis to identify the proteins involved in the compensatory mechanism induced by paclitaxel in HeyA8 and SKOV3 ovarian cancer cells. We used a cell viability assay to examine whether inhibition of the proteins involved in the compensatory adaptive response influenced the effects of paclitaxel on cancer cell viability. All experiments were performed in three-dimensional cell cultures.ResultsPaclitaxel induced the upregulation of pS6 (S240/S244) and pS6 (S235/S236) in HeyA8 and SKOV3 cells, and pPRAS40 (T246) in HeyA8 cells. BX795 and CCT128930 were chosen as inhibitors of pS6 (S240/S244), pS6 (S235/S236), and pPRAS40 (T246). BX795 and CCT128930 decreased pS6 (S240/S244) and pS6 (S235/S236) expression in HeyA8 and SKOV3 cells. However, pPRAS40 (T246) expression was inhibited only by BX795 and not by CCT128930 in HeyA8 cells. Compared with paclitaxel alone, addition of BX795 or CCT128930 to paclitaxel was more effective in decreasing the viability of HeyA8 and SKOV3 cells.ConclusionAddition of BX795 or CCT128930 to inhibit pS6 (S240/S244) or pS6 (S235/S236) restricted the compensatory adaptive response to paclitaxel in HeyA8 and SKOV3 cells. These inhibitors increased the efficacy of paclitaxel in reducing cancer cell viability.

Fucosterol Suppresses the Progression of Human Ovarian Cancer by Inducing Mitochondrial Dysfunction and Endoplasmic Reticulum Stress

“…The mTOR/p70S6K pathway is activated in ovarian cancer, and carboplatin inhibits the growth of ovarian cancer cells through suppression of mTOR/p70S6K [31]. Activation of the MEK-S6 pathway is also observed in high-grade ovarian cancers [32], and suppression of p-S6 increased the anti-cancer effect of paclitaxel in ovarian cancer cells [33]. In our results, fucosterol inhibited the expression of p-P70S6K and p-S6.…”

Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies

“…These adaptive responses indicate both mechanisms of resistance and therapeutic opportunities. We and others have demonstrated that combination therapy designed to capitalize on adaptive responses induced by therapy can generate tumor control in preclinical model systems [13][14][15][16][17][18][19][20][21][22][23] . We have translated many of these observations to clinical trials, with marked patient benefit (NCT03162627, NCT02208375, NCT02659241, NCT03586661, NCT02316834, NCT03544125, NCT03801369, and NCT03637491).…”

Dual inhibition of FOXM1 and its compensatory signaling pathway decreased the survival of ovarian cancer cells

“…Many patients with stage III or IV ovarian cancer who show complete response to frontline treatment eventually show high recurrence rates (3). Several studies have focused on lowering the high recurrence and drug-resistance rates and improving survival of patients with ovarian cancer (4,5). The Cancer Genome Atlas project has analyzed mRNA expression, microRNA expression, promoter methylation and DNA copy number in high-grade serous ovarian cancer tissues, and pathway analyses suggested that forkhead box protein M1 (FOXM1) signaling is involved in serous ovarian cancer pathophysiology (4).…”

“…The major obstacle in the management of ovarian cancer is drug resistance, and compensatory adaptive response is one of the mechanisms that cause drug resistance (5,9). This response in cancer cells modulated the cell signaling pathway related to cell survival and activates the drug resistance process, which ultimately can lead to the survival of cancer cells during drug therapy.…”