Src homology phosphotyrosyl phosphatase 2 mediates cisplatin-related drug resistance by inhibiting apoptosis and activating the Ras/PI3K/Akt1/survivin pathway in lung cancer cells

Abstract

Cisplatin resistance is a major cause of chemotherapeutic failure in lung cancer patients. Unraveling the molecular mechanisms underlying cisplatin (CDDP) resistance is important in lung cancer therapeutics. To explore the role of Src homology phosphotyrosyl phosphatase 2 (SHP2) in the development of cisplatin resistance in lung cancer and the underlying mechanism, we established stable SHP2‑overexpressing H446‑SHP2-OE cells and SHP2‑knockdown H446/CDDP‑SHP2-shRNA cells derived from H446 and H446/CDDP (cisplatin-resistant) parental lung cancer cells. The cell viability and apoptosis of these cells exposed to CDDP were observed to determine the influence of SHP2 on drug resistance. In addition, the expression of SHP2, Ras, Akt1 and survivin was assessed by western blot analysis after the lung cancer cells were challenged by cisplatin or silenced by Ras siRNA. As a result, the 50% inhibitory concentration (IC50) of the H446-SHP2-OE cells exposed to CDDP increased from 1.01 to 1.218 µg/ml vs. the H446-control vector cells. The percentage of apoptotic cells was smaller in the H446-SHP2-OE cells vs. the H446-control vector cells after cisplatin challenge. In addition, the expression of Ras, pAkt1, Akt1 and survivin in the H446/CDDP cells was significantly increased vs. the H446 cells. Furthermore, the IC50 of the H446/CDDP‑SHP2‑shRNA cells exposed to CDDP decreased from 11.92 to 4.382 µg/ml vs. the H446/CDDP‑mock cells. There were significantly more apoptotic cells among the H446/CDDP‑SHP2-shRNA cells vs. the H446/CDDP-mock cells exposed to cisplatin. A smaller percentage of the H446/CDDP-SHP2-shRNA cells vs. the H446/CDDP‑mock cells was observed. In addition, the expression of pAkt1 and survivin in the H446, H446/CDDP and H446/CDDP-mock cells was increased upon exposure to cisplatin however, a corresponding change was not observed in the H446/CDDP-SHP2-shRNA cells. Upon Ras RNA silencing with cisplatin, the Ras expression was significantly decreased in the H446, H446-SHP2-OE and H446/CDDP cells. However, upon Ras RNA interference, the SHP2 expression was not significantly changed, but the expression of Akt1, pAkt1 and survivin was significantly increased in the H446-SHP2-OE and H446/CDDP cells. In conclusion, SHP2 is a new cisplatin resistance-related phosphatase in lung cancer, which inhibits apoptosis by activating the Ras/PI3K/Akt1/survivin signaling pathway.

Quercetin Inhibits the Proliferation and Metastasis of Human Non-Small Cell Lung Cancer Cell Line: The Key Role of Src-Mediated Fibroblast Growth Factor-Inducible 14 (Fn14)/ Nuclear Factor kappa B (NF-κB) pathway

“…The abnormally high level of Src is always associated with the progression of NSCLC, especially for smoking patients [7,12]. Previous studies have indicated that the pro-NSCLC function of Src is exerted through multipronged mechanisms: the abnormally high expression of Src contributes to the activation of Fn-14-mediated NF-kB [13] and Ras/PI3K/Akt signaling [14]. Thus, it is reasonable to develop anti-NSCLC therapies by specifically inhibiting the function of Src.…”

Effect and Mechanism of Survivin on Hypoxia-Induced Multidrug Resistance of Human Laryngeal Carcinoma Cells

“…Previously, our study has also confirmed that upregulation of survivin expression was significantly associated with decreased apoptosis index in human laryngeal squamous cell carcinoma tissues [12], further sustaining the notion that survivin is involved in the regulation of laryngeal cancer cells apoptosis. Furthermore, several literatures have shown that survivin plays a key role in regulating drug resistance by its biologic function of resistance to apoptosis in multiple types of neoplasias [23, 24]. In this series, our work demonstrated that blocking survivin expression could significantly promote the apoptosis induced by cisplatin or paclitaxel in hypoxic laryngeal carcinoma cells, reversing drug resistance.…”

The Importance of Being PI3K in the RAS Signaling Network

“…K-RasK-Ras mutations induce NRF2 transcription and pathway upregulation, resulting in the overactivation of the anti-oxidative stress pathway, rendering tumor cells resistant to cisplatin-induced ROS [ 257 , 260 ]. In lung cancer cell lines, SHP2 mediates cisplatin-resistance-related phosphatase in a process that involves the inhibition of apoptosis by the activation of Ras/PI3K/AKT/survivin signaling pathway, and, consequently, the inhibition of SHP2 was associated with reduced expression of Ras, AKT, AKT activation, and survivin [ 261 ]. In ovarian cancer cell lines, crosstalk between STAT3 and Ras/p53 activated PI3K and ERK pathways, which in turn inhibited endoplasmic reticulum stress (ERS)-associated molecules, blocking cellular autophagy and inducing cisplatin resistance [ 262 ].…”