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
Authors: Hu Luo
Dan Luo
Chunlan Tang
Xiangdong Zhou
Heping Yang
Journal: Oncology Reports (2017)
Discipline: CLINICAL MEDICINE
Keywords: Cisplatin resistance; lung cancer; SHP2; Ras; Akt1
Affiliations: Department of Respiratory Medicine, The First Affiliated Hospital of The Third Military Medical University, Shapingba, Chongqing 400038, P.R. China

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. 

Retracted: No

PubPeer comments:
 Figure 10A was brought to my attention by a reader. * Green boxes: In the HE row, the L-PRP+CAPE and P-PRP panels appear to show an overlap if one of the images is in mirror image. ![file] , 
 Dear Dr. Elisabeth M. Bik, Thank you for informing me of the figure 10A problem. I am totally shocked. It is absolutely an extremely serious problem if there is any academic misconduct. I have made it my highest priority and am about to contact other authors immediately to investigate the problem. The manuscript, raw data and the process of data management will be re-examined carefully as soon as possible. I will post the investigation results and keep you updated. Thank you again for pointing out the figure problem. And thank the reader, too. Xuetao Xie ,