miR-200c enhances sensitivity of drug-resistant non-small cell lung cancer to gefitinib by suppression of PI3K/Akt signaling pathway and inhibites cell migration via targeting ZEB1.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a major obstacle in the treatment of non-small cell lung cancer (NSCLC) patients. We explored the role of miR-200c in modulating the sensitivity of gefitinib-resistant NSCLC cells and examined the underlying mechanism. The gefitinib-resistant cell line PC-9-ZD and its parental PC-9 cells were used. Growth inhibition was detected by MTT assay. The cell apoptosis was detected by Annexin V/PI assay. Cell migration was assessed by wound-healing assay. RT-PCR was used to detected levels of miR-200c and ZEB1. The PI3k, Bcl-2, Bax, caspase-3 and ZEB1 protein expression were detected using Western blot analysis, and TUNEL, Immunohistochemistry for xenograft model. PC-9-ZD cells had low level of miR-200c expression compared to its parental PC-9 cells. PC-9-ZD cells with miR-200c transfection were more sensitive to gefitinib treatment. Apoptosis induced by gefitinib was observed in PC-9-ZD cells with miR-200c transfection significantly. The levels of phosphorylated-Akt and Bcl-2 expression decreased and levels of Bax and Caspase-3 expression increased in PC-9-ZD cells with miR-200c transfection. Cell migration was inhibited and ZEB1 mRNA level and protein expression were significantly decreased in PC-9-ZD cells with miR-200c transfection. Further in gefitinib resistant xenograft model, miR-200c enhanced sensitivity of gefitinib and induced apoptosis significantly through PI3K/Akt signaling pathway and targeting ZEB1. These results provided insights into the functions of miR-200c and offered an alternate approach in treating gefitinib-resistance NSCLC.

Zhou G ，Zhang F ，Guo Y ，Huang J ，Xie Y ，Yue S ，Chen M ，Jiang H ，Li M ... -  《-》

Polyphyllin II Restores Sensitization of the Resistance of PC-9/ZD Cells to Gefitinib by a Negative Regulation of the PI3K/Akt/mTOR Signaling Pathway.

EGFR tyrosine kinase inhibitors (TKIs) are widely used for advanced nonsmall cell lung cancer (NSCLC) patients with a sensitizing EGFR mutation and provide a promising treatment strategy. However, acquired resistance to EGFR-TKIs restricts their application. The mechanisms underlying acquired resistance to TKIs have been explored and Phosphoinositide 3- kinase (PI3K)/Akt/mTOR pathway plays a very important role in NSCLC development as well as EGFR-TKI resistance. Polyphyllin II(PP II) is the main steroidal saponin constituent which derives from the root of Paris polychylia. We examined the sensitizing effect of PP II to gefitinib on proliferation, apoptosis, PI3K/Akt/mTOR signaling pathway and tumor growth on gefitinib-resistant NSCLC in vitro and in vivo. Gefitinib-resistant PC-9/ZD cells and gefitinib-sensitive PC-9 cells were used. In the absence of PI3K siRNA, MTT assay, Annexin V/PI analyses, Western blot, and Immunohistochemistry analysis by TUNEL assays for xenograft model were carried out. PP II promoted the anti-proliferative effects of gefitinib and gefitinib-induced apoptosis via activation of caspases and cleavage of PARP. PP II elevated sensitization of gefitinib through targeting the PI3K/Akt/mTOR. PP II with gefitinib treatment was more effective in inhibiting tumor growth and PI3K inactivation on gefitinib-resistant xenograft. The results indicated that PP II elevated sensitization of drug-resistant PC-9/ZD cells to gefitinib through the inhibition of PI3K/Akt/mTOR signaling pathway. It provides a potential new strategy to overcome gefitinib resistance for EGFR-TKI resistant NSCLC.

Zheng R ，Jiang H ，Li J ，Liu X ，Xu H ... -  《-》

Anticancer Effects of Paris Saponins by Apoptosis and PI3K/AKT Pathway in Gefitinib-Resistant Non-Small Cell Lung Cancer.

Zhu X ，Jiang H ，Li J ，Xu J ，Fei Z ... -  《MEDICAL SCIENCE MONITOR》

Chronic treatment of non-small-cell lung cancer cells with gefitinib leads to an epigenetic loss of epithelial properties associated with reductions in microRNA-155 and -200c.

Narita M ，Shimura E ，Nagasawa A ，Aiuchi T ，Suda Y ，Hamada Y ，Ikegami D ，Iwasawa C ，Arakawa K ，Igarashi K ，Kuzumaki N ，Yoshioka Y ，Ochiya T ，Takeshima H ，Ushijima T ，Narita M ... -  《PLoS One》

MiR-128 reverses the gefitinib resistance of the lung cancer stem cells by inhibiting the c-met/PI3K/AKT pathway.

Jiang J ，Feng X ，Zhou W ，Wu Y ，Yang Y ... -  《Oncotarget》