Liver X receptors agonist GW3965 re-sensitizes gefitinib-resistant human non-small cell lung cancer cell to gefitinib treatment by inhibiting NF-κB in vitro

Abstract

The recent research shows that the inhibition of the nuclear factor-κB (NF-κB) pathway is a promising therapeutic option for patients who progress after treatment with the novel mutant-selective EGFR-TKIs. For propose to find a nontoxic drug to reverse the acquired gefitinib resistance, we examined whether the Liver X Receptors agonist GW3965 affect gefitinib resistance of HCC827/GR-8-2 cells. Cell viability was measured by CCK-8 assay. Levels of NF-κB, p-AKT and caspases were detected by Western blot analysis. Immunocytochemical analysis was used to detect the expression of NF-κB, p-AKT intracellularly. Induction of apoptosis and cell cycle arrest was measured by Flow cytometry assay. And results revealed that more than 90% of HCC827/GR-8-2 cells lived upon treatment with gefitinib at a dose of 5μM for 48h. However, when under the combine treatment of GW3965 (5μM) & gefitinib(5μM), cell death rate was increased observably. Co-administration of gefitinib & GW3965 induced cell apoptosis and cell cycle arrest. Additionally, we observed a dose-dependent- down-regulation of NF-κB in HCC827/GR-8-2 cells treated with gefitinib & GW3965. GW3965 and gefitinib synergistically decreased cell proliferation and induced apoptosis by inhibiting NF-κB signaling pathway in gefitinib resistant cells. These findings support our hypothesis that GW3965 could act as a useful drug to reverse the gefitinib resistance.

Efatutazone and T0901317 exert synergistically therapeutic effects in acquired gefitinib‐resistant lung adenocarcinoma cells

“…Moreover, in HCC827-GR and PC9-GR cells, we also showed that with PPARγ expression stable, si-LXRα depressed LXRα and ABCA1 expression levels, which approved that LXRα is a downstream target gene of the PPARγ, consistent with previous reports [31]. There was another report that the lung adenocarcinoma cells proliferation could be restrained by LXRα activation [22]. Therefore, cancer cells proliferation may be increased followed by LXRα and ABCA1 inactivated.…”

“…In the process of initiation and development of lung adenocarcinoma, the expressions of PPAR, LXR, and ABCA1 were decreasing. On the other hand, the lung adenocarcinoma cells proliferation could be inhibited by the over expression of the three genes above .Our findings that efatutazone elevated the expression of PPAR γ , LXR α , and ABCA1 further proved that efatutazone participates in PPAR γ /LXR α /ABCA1 pathway in HCC827‐GR and PC9‐GR cells.…”

“…According to previously reported method, HCC827 and PC9 cells were exposed to increasing the concentration of gefitinib in order to establish gefitinib-resistant subline cells [22]. Ultimately, HCC827 and PC-9 cells produced stable gefitinib resistance: isolated HCC827-GR and PC9-GR cell lines were confirmed to resistant to gefitinib independently.…”

Effects of microRNA‐513b on cell proliferation, apoptosis, invasion, and migration by targeting HMGB3 through regulation of mTOR signaling pathway in non‐small‐cell lung cancer

“…miRNAs play critical roles in multiple human cancers, such as colorectal cancer (Liang et al, 2015), gallbladder cancer (Ma et al, 2015), as well as lung cancer (Hu et al, 2017). MiR-513b is a member of miR-513 subfamily, which belongs to an X-linked primate-specific miR506-514 cluster (Sun et al, 2013).…”

Targeting Nuclear Receptors in Lung Cancer—Novel Therapeutic Prospects

“…GW3965 has previously been found to decrease NF-κB transcriptional activity [ 280 ]. The findings of a report have supported that GW3965 could be an effective treatment for gefitinib resistance [ 281 ]. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature granulocytic and monocytic cells that are important components of the tumor microenvironment (TME).…”