Journal
CELLS
Volume 9, Issue 8, Pages -Publisher
MDPI
DOI: 10.3390/cells9081830
Keywords
colorectal cancer (CRC); gefitinib; NDAT; PD-L1; PI3K
Categories
Funding
- Shuang-Ho Hospital Collaborating Program [102TMU-SHH-05]
- Ministry of Education (MOE) in Taiwan [DP2-107-20000]
- Ministry of Science and Technology Taiwan [MOST 107-2314-B-038-017, MOST108-2314-B-038-050, MOST108-2119-038-001]
- National Institute of Food and Agriculture [CA-D*-MCB-7399-H]
- NIH [UG3TR002866, AI095382, EB021230, CA198880]
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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 ofPD-L1and 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)ThePD-L1was highly expressed in Colo_160224 rather than in the other three primary CRC cells and HCT-116 cells. Moreover, thePD-L1expression was decreased by gefitinib (1 mu M and 10 mu M) in two cells (Colo_150624 and 160426), but 10 mu M gefitinib stimulatedPD-L1expression in gefitinib-resistant primary CRC Colo_160224 cells. Inactivated PI3K reducedPD-L1expression and proliferation in CRC Colo_160224 cells. Gefitinib didn't inhibitPD-L1expression 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-RASmutant) xenograft experiment.(4)Gefitinib might suppressPD-L1expression 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.
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