Abstract
The property of drug-resistance may attenuate clinical therapy in cancer cells, such as chemoresistance to gefitinib in colon cancer cells. In previous studies, overexpression of PD-L1 causes proliferation and metastasis in cancer cells; therefore, the PD-L1 pathway allows tumor cells to exert an adaptive resistance mechanism in vivo. Nano-diamino-tetrac (NDAT) has been shown to enhance the anti-proliferative effect induced by first-line chemotherapy in various types of cancer, including colorectal cancer (CRC). In this work, we attempted to explore whether NDAT could enhance the anti-proliferative effect of gefitinib in CRC and clarified the mechanism of their interaction. The MTT assay was utilized to detect a reduction in cell proliferation in four primary culture tumor cells treated with gefitinib or NDAT. The gene expression of PD-L1 and other tumor growth-related molecules were quantified by quantitative polymerase chain reaction (qPCR). Furthermore, the identification of PI3K and PD-L1 in treated CRC cells were detected by western blotting analysis. PD-L1 presentation in HCT116 xenograft tumors was characterized by specialized immunohistochemistry (IHC) and the hematoxylin and eosin stain (H&E stain). The correlations between the change in PD-L1 expression and tumorigenic characteristics were also analyzed. (3) The PD-L1 was highly expressed in Colo_160224 rather than in the other three primary CRC cells and HCT-116 cells. Moreover, the PD-L1 expression was decreased by gefitinib (1 µM and 10 µM) in two cells (Colo_150624 and 160426), but 10 µM gefitinib stimulated PD-L1 expression in gefitinib-resistant primary CRC Colo_160224 cells. Inactivated PI3K reduced PD-L1 expression and proliferation in CRC Colo_160224 cells. Gefitinib didn’t inhibit PD-L1 expression and PI3K activation in gefitinib-resistant Colo_160224 cells. However, NDAT inhibited PI3K activation as well as PD-L1 accumulation in gefitinib-resistant Colo_160224 cells. The combined treatment of NDAT and gefitinib inhibited pPI3K and PD-L1 expression and cell proliferation. Additionally, NDAT reduced PD-L1 accumulation and tumor growth in the HCT116 (K-RAS mutant) xenograft experiment. (4) Gefitinib might suppress PD-L1 expression but did not inhibit proliferation through PI3K in gefitinib-resistant primary CRC cells. However, NDAT not only down-regulated PD-L1 expression via blocking PI3K activation but also inhibited cell proliferation in gefitinib-resistant CRCs.
Highlights
In recent years, colorectal cancer (CRC) has been recognized as the third most prevalent and fourth most lethal cancer worldwide [1]
We studied the role of activated Phosphoinositide 3-kinase (PI3K) on the programmed death-ligand 1 (PD-L1) expression and cancer growth in CRC primary cultures and K-RAS mutant HCT116 cell xenografts
We investigated the effects of NDAT and gefitinib in primary
Summary
Colorectal cancer (CRC) has been recognized as the third most prevalent and fourth most lethal cancer worldwide [1]. The incidence of this cancer has rapidly increased in the past 10 years in Taiwan (4576 cases/106 population in 2002 vs 9299 cases/106 population in 2012) [2]. Mutations of Adenomatous Polyposis Coli (APC), K-RAS, and β-catenin genes have been proposed as early events in the tumorigenesis of CRC [3,4], but whether relationships exist among such events is unclear. Aberrant activation of EGFR stimulates several intracellular signaling pathways—Phosphoinositide 3-kinase (PI3K)/AKT, RAS/RAF/MEK/ERK, Src/signal transducer and activator of transcription (STAT)—Which in turn cause augmented cell proliferation and other oncogenic characteristics in cancers [6]. Low EGFR expression in CRC cells is correlated clinically with low tumor metastasis risk and better survival [4,7]
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