ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling

Abstract

Background: Lung cancer (LC) is still the most common cause of cancer related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all LC cases but is not a single entity. It is now accepted that, apart from the characteristic driver mutations, the unique molecular signatures of adeno-(AC) and squamous cell carcinomas (SCC), the two most common NSCLC subtypes should be taken into consideration for their management. Therapeutic interventions, however, frequently lead to chemotherapy resistance highlighting the need for in-depth analysis of regulatory mechanisms of multidrug resistance to increase therapeutic efficiency. Methods: Non-canonical Wnt5a and canonical Wnt7b and ABC transporter expressions were tested in primary human LC (n = 90) resections of AC and SCC. To investigate drug transporter activity, a three dimensional (3D) human lung aggregate tissue model was set up using differentiated primary human lung cell types. Following modification of the canonical, beta-catenin dependent Wnt pathway or treatment with cisplatin, drug transporter analysis was performed at mRNA, protein and functional level using qRT-PCR, immunohistochemistry, immune-fluorescent staining and transport function analysis. Results: Non-canonical Wnt5a is significantly up-regulated in SCC samples making the microenvironment different from AC, where the beta-catenin dependent Wnt7b is more prominent. In primary cancer tissues ABCB1 and ABCG2 expression levels were different in the two NSCLC subtypes. Non-canonical rhWnt5a induced down-regulation of both ABCB1 and ABCG2 transporters in the primary human lung aggregate tissue model recreating the SCC-like transporter pattern. Inhibition of the beta-catenin or canonical Wnt pathway resulted in similar down-regulation of both ABC transporter expression and function. In contrast, cisplatin, the frequently used adjuvant chemotherapeutic agent, activated beta-catenin dependent signaling that lead to up-regulation of both ABCB1 and ABCG2 transporter expression and activity.

Cardamonin Enhances Cisplatin Chemosensitivity of Nasopharyngeal Cancer Cells via Attenuating c-Myc-Mediated β-Catenin/ABCG2 Signaling

“…It is crucial to understand the occurrence of chemoresistance, and eventually how to prevent it for combatting cancer effectively [8,27,28], and it is well known that the ABC transporter family are implicated in multidrug resistance and high-expressed levels of ABCG2 have a greater capacity to expel therapeutic drugs [25,29,30]. Furthermore, accumulating ndings reveal that aberrant Wnt/β-catenin signaling and increased ABCG2 expression are closely correlated to multidrug resistance in many cancers [14,15,31], including NPC [18,17]. Also, ABCG2 was reported as a downstream gene of β-catenin since its seven functional transcription factor binding sites have been identi ed in the ABCG2 gene promoter [16].…”

“…Increasing evidence indicates that the Wnt/β-catenin signaling is closely correlated to DPP resistance in several human tumors [10,11,12]. Moreover, abnormal Wnt/β-catenin signaling activation contributes to upregulation of drug e ux ABC transporters in many cancer types [13,14,15,16], including NPC [17].…”

An optical study of drug resistance detection in endometrial cancer cells by dynamic and quantitative phase imaging

“…Cisplatin is one of the most commonly used chemotherapies in gynecologic oncology. Unfortunately, many cancers initially respond well to platinum treatment but often develop resistance when tumors recur . Until now, studies have shown that increased DNA repair, altered cellular accumulation, and increased drug inactivation are the main reasons for cells to acquire drug resistance .…”

Function of insulin‑like growth factor 1 receptor in cancer resistance to chemotherapy (Review)

“…Nuclear IGF1R specifically binds to and functions as a transcriptional activator of its own promoter, and interferes with signaling pathways (98). Specifically, nuclear IGF1R interferes with Wnt signaling, which upregulates ABC drug transporters and modulates drug responses (99). Regarding the tumor microenvironment, activating IGF1R results in stabilizing hypoxia-inducible factor (HIF)-1α and HIF-2α, and the upregulation of vascular endothelial growth factor (100).…”