DCLK1 Regulates Tumor Stemness and Cisplatin Resistance in Non-small Cell Lung Cancer via ABCD-Member-4

Abstract

Chemoresistance cells have features similar to cancer stem cells. Elimination of these cells is an effective therapeutic strategy to clinically combat chemoresistance non-small cell lung cancer (NSCLC). Here, we demonstrate that <i>Doublecortin-like kinase1</i> (<i>DCLK1</i>) is the key to developing chemoresistance and associated stemness in NSCLC. DCLK1 is highly expressed in human lung adenocarcinoma and strongly correlated with stemness. Silencing <i>DCLK1</i> inhibits NSCLC cell primary and secondary spheroid formation, which is the prerequisite feature of tumor stem cells. <i>DCLK1</i> inhibition reduced NSCLC cell migration/invasion <i>in vitro</i> and induced tumor growth inhibition <i>in vivo</i>. NSCLC cells responded differently to cisplatin treatment; indeed, the clonogenic ability of all NSCLC cells was reduced. We found that the cisplatin-resistant NSCLC cells gain the expression of DCLK1 compared with their parental control. However, <i>DCLK1</i> inhibition in cisplatin-resistance NSCLC cells reverses the tumor cell resistance to cisplatin and reduced tumor self-renewal ability. Specifically, we found that <i>DCLK1</i>-mediated cisplatin resistance in NSCLC is via an <i>ABC subfamily member 4</i> (<i>ABCD4</i>)-dependent mechanism. Our data demonstrate that increased expression of <i>DCLK1</i> is associated with chemoresistance and enhanced cancer stem cell-like features in NSCLC. Targeting <i>DCLK1</i> using gene knockdown/knockout strategies alone or in combination with cisplatin may represent a novel therapeutic strategy to treat NSCLC.