Akademik Veri Yönetim Sistemi
BIOLOGY-BASEL, cilt.9, sa.10, ss.1-18, 2020 (SCI-Expanded)
Simple Summary Investigation into effective targets of drug resistance is important for identifying novel strategies in cancer therapy. The study aimed to determine the functional role of paclitaxel (PTX) resistance on MCF-7 cell survival related to PI3K/Akt and MAPK pathways. Therefore, we generated PTX-resistant (PTX-res) MCF-7 cells exposed to increasing concentrations of PTX (5-100 nM) over a period of 6 months. Increased cell survival, proliferation, and colony formations were observed in PTX-res MCF-7 cells, while survival inhibition was determined in non-resistant wt cells. PTX-res MCF-7 cells appeared morphologically different from wt cells with their star-like shape which showed the mesenchymal characteristics of cells. Active PI3K/Akt signaling and increased motility were confirmed by upregulation of the EMT pathway members in PTX-res MCF-7 cells. We suggested that the active Akt signaling was related to the upregulated stress-mediated activation of MAPK signaling members, as shown by the significant p38 and SAPK/JNK activation in our results. To sensitize PTX-res MCF-7 cells we treated wt and PTX-res MCF-7 cells with specific c-Jun N-terminal kinase inhibitor, JNK-IN-8, and significant suppression on p38, SAPK/JNK expression was observed. Wnt signaling was highly affected by JNK inhibition. We concluded that JNK inhibition is a potential target to reverse PTX-resistance related to Wnt signaling. Paclitaxel (PTX) is a widely used chemotherapeutic agent in the treatment of breast cancer, and resistance to PTX is a common failure of breast cancer therapy. Therefore, understanding the effective molecular targets in PTX-resistance gains importance in identifying novel strategies in successful breast cancer therapy approaches. The aim of the study was to investigate the functional role of PTX resistance on MCF-7 cell survival and proliferation related to PI3K/Akt and MAPK pathways. The generated PTX-resistant (PTX-res) MCF-7 cells showed enhanced cell survival, proliferation, and colony formation potential with decreased cell death compared to wt MCF-7 cells. PTX-res MCF-7 cells exhibited increased motility profile with EMT, PI3K/Akt, and MAPK pathway induction. According to the significant SAPK/JNK activation in PTX-res MCF-7 cells, specific c-Jun N-terminal kinase inhibitor, JNK-IN-8 is shown to suppress the migration potential of cells. Treatment of JNK inhibitor suppressed the p38 and SAPK/JNK and Vimentin expression. However, the JNK inhibitor further downregulated Wnt signaling members in PTX-res MCF-7 cells. Therefore, the JNK inhibitor JNK-IN-8 might be used as a potential therapy model to reverse PTX-resistance related to Wnt signaling.