HIF-1-Dependent Heme Synthesis Promotes Gemcitabine Resistance In Human Non-Small Cell Lung Cancers Via Enhanced ABCB6 Expression

Background: Gemcitabine, a deoxycytidine analogue, is commonly used in the treatment of various types of tumors, including human non-small cell lung cancer (NSCLC). However, even the initial responders rapidly develop acquired resistance which limits our ability to effectively treat advanced NSCLC. The present study reports a widely prevalent mechanism of resistance to gemcitabine in NSCLC, whereby induced expression of ABCB6 is associated with poor prognosis and gemcitabine resistance in human NSCLCs which is in a HIF-1-dependent manner. Methods: We established gemcitabine resistant LUSC and LUAD cells and examined ABCB6 expression as well as heme synthesis in these cells. Additionally, we analyzed catalase protein expression and activity in gemcitabine resistant NSCLC cell lines. To validate ABCB6 gene as an HRE, we performed ChIP-qPCR assay. We also investigated the effect of inhibition of HIF-α/ABCB6 axis in vitro and in vivo . Results: The activation of HIF-1α/ABCB6 signaling leading to intracellular heme metabolic reprogramming and a corresponding increase in heme biosynthesis to enhance the activation and accumulation of catalase. Increased levels of catalase diminish the effective levels of reactive oxygen species (ROS) promoting gemcitabine-based resistance. Targeting HIF-1α or ABCB6, in combination with gemcitabine, strongly restrains tumor proliferation, increases tumor cell apoptosis and prolongs animal survival. Conclusion: In combination with gemcitabine-based chemotherapy, targeting HIF-1α/ABCB6 signaling could result in enhanced tumor sensitivity to chemotherapeutic agent and may improve outcome in NSCLCs.