Sulfasalazine Suppresses Drug Resistance and Invasiveness of Lung Adenocarcinoma Cells Expressing AXL

Abstract

Metastasis and drug resistance are the major causes of mortality in patients with non-small cell lung cancer (NSCLC). Several receptor tyrosine kinases (RTKs), including AXL, are involved in the progression of NSCLC. The AXL/MER/SKY subfamily is involved in cell adhesion, motility, angiogenesis, and signal transduction and may play a significant role in the invasiveness of cancer cells. Notably, no specific inhibitors of AXL have been described. A series of CL1 sublines with progressive invasiveness established from a patient with NSCLC has been identified that positively correlates with AXL expression and resistance to chemotherapeutic drugs. The ectopic overexpression of AXL results in elevated cell invasiveness and drug resistance. Nuclear factor-KB (NF-KB) signaling activity is associated with AXL expression and may play an important role in the enhancement of invasiveness and doxorubicin resistance, as shown by using the NF-KB inhibitor, sulfasalazine, and IKB dominant-negative transfectants. In the current study, sulfasalazine exerted a synergistic anticancer effect with doxorubicin and suppressed cancer cell invasiveness in parallel in CL1 sublines and various AXL-expressing cancer cell lines. Phosphorylation of AXL and other RTKs (ErbB2 and epidermal growth factor receptor) was abolished by sulfasalazine within 15 min, suggesting that the inhibition of NF-KB and the kinase activity of RTKs are involved in the pharmacologic effects of sulfasalazine. Our study suggests that AXL is involved in NSCLC metastasis and drug resistance and may therefore provide a molecular basis for RTK-targeted therapy using sulfasalazine to enhance the efficacy of chemotherapy in NSCLC. [Cancer Res 2007;67(8):3878-87]

Axl promotes cell invasion by inducing MMP-9 activity through activation of NF-κB and Brg-1

“…Our present observation provides the first evidence that NF-kB activity is essential for an efficient Axl-mediated invasion of cancer cells by secreting MMP-9. This mechanism is consistent with the aberrant activation of Axl and NF-kB associated with malignant properties in cancer cells (Budagian et al, 2005;Vajkoczy et al, 2006;Lay et al, 2007).…”

“…In contrast to the role of NF-kB stimulated by the Gas6/Axl system in vascular biology, the possibility that the Axl-driven NF-kB activity plays a role in tumor cells, especially in cancer metastasis, remains to be determined. A positive correlation between Axl-induced cell invasion and NF-kB activity was identified in human non-small cell lung cancer (Lay et al, 2007). Inhibition of NF-kB activity with the NF-kB inhibitor sulfasalazine in nonsmall cell lung cancer cells disrupts chemoresistance and cell invasiveness.…”

AXL regulates mesothelioma proliferation and invasiveness

“…Various recent studies implicate AXL as an oncogenic factor in advanced solid tumors: AXL is overexpressed in highly invasive lung adenocarcinoma cell lines, metastatic DU145 prostate cancer models and metastatic colon tumors (Craven et al, 1995;Jacob et al, 1999;Shieh et al, 2005). These and other studies suggest that AXL overexpression promotes invasiveness (Lay et al, 2007;Tai et al, 2008;Li et al, 2009). We show that in vitro mesothelioma migration and invasion are inhibited by AXL antagonists, either by AXL shRNA knockdown or the DP-3975 small-molecular inhibitor of AXL kinase activity (Figures 5a, b and c).…”

TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer

“…Axl RTK is expressed in lung adenocarcinoma cell lines, and the level of Axl expression correlates with the invasive ability of these cell lines in vitro (Lay et al, 2007;Shieh et al, 2005). Ectopic overexpression of Axl in adenocarcinoma cell lines leads to increased formation of filipodia, migration, and drug resistance.…”