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(S)-crizotinib reduces gastric cancer growth through oxidative DNA damage and triggers pro-survival akt signal.

ABSTRACT: Gastric cancer (GC), a common gastrointestinal malignancy worldwide, has poor prognosis and frequent recurrence. There is a great need to identify effective therapy for GC. Crizotinib is a multi-targeted, clinically available oral tyrosine kinase inhibitor approved for lung cancer, but its use for the highly heterogeneous disease of GC is unknown. The goal of this study was to investigate the anti-cancer mechanisms of the (S)-crizotinib in inhibiting GC growth. Human GC cell lines (SGC-7901 and BGC-823) and the (S)-crizotinib-resistant BGC-823/R were cultured for determining the effects of (S)-crizotinib on cell viability, apoptosis, oxidant generation, and cell cycle progression. Involvement of ROS, Akt signaling, MTH1, and DNA damage was tested with respective pharmacological blockade. The in vivo anti-tumor effects of (S)-crizotinib were determined using xenograft tumor mice. Results indicated that (S)-crizotinib decreased GC cell viability, induced growth arrest and apoptosis, and increased levels of ?H2AX and Ser1981-phosphorylated ATM, which were inhibited by NAC. The anti-cancer mechanism of (S)-crizotinib was independent of MTH1. Moreover, ATM-activated Akt, a pro-survival signal, whose inhibition further enhanced (S)-crizotinib-induced inhibition of GC cell growth and tumor growth in xenograft mice, and re-sensitized resistant GC cells to (S)-crizotinib. (S)-crizotinib reduced GC cell and tumor growth through oxidative DNA damage mechanism and triggered pro-survival Akt signaling. We conclude that inclusion of Akt inhibition (to block the survival signaling) with (S)-crizotinib may provide an effective and novel combination therapy for GC in the clinical setting.

SUBMITTER: Ji J

PROVIDER: S-EPMC5981313 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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(S)-crizotinib reduces gastric cancer growth through oxidative DNA damage and triggers pro-survival akt signal.

Ji Jiansong J Chen Weiqian W Lian Weishuai W Chen Ruijie R Yang Jinqing J Zhang Qianqian Q Weng Qiaoyou Q Khan Zia Z Hu Jie J Chen Xi X Zou Peng P Chen Xiaoming X Liang Guang G

Cell death & disease 20180531 6

Gastric cancer (GC), a common gastrointestinal malignancy worldwide, has poor prognosis and frequent recurrence. There is a great need to identify effective therapy for GC. Crizotinib is a multi-targeted, clinically available oral tyrosine kinase inhibitor approved for lung cancer, but its use for the highly heterogeneous disease of GC is unknown. The goal of this study was to investigate the anti-cancer mechanisms of the (S)-crizotinib in inhibiting GC growth. Human GC cell lines (SGC-7901 and ...[more]

PMID: 29855474

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Project description:BackgroundThe primary objective of this investigation was to assess the impact of pyrroline-5-carboxylate reductase 1 (PYCR1) on the progression of gastric cancer (GC), specifically focusing on tumor growth and metastatic potential.MethodsSurgical specimens from patients with different stages of GC were assayed for PYCR1 expression using immunohistochemistry. PYCR1 expression was manipulated by depletion or overexpression approaches in GC cells, and these cells were applied to explore the functional roles of PYCR1. Expression of apoptosis- and metastasis-related markers was quantified through quantitative real-time PCR and Western blot.ResultsHigher PYCR1 expression was ascertained in surgical specimens from patients with GC as compared to noncancerous adjacent tissues. Additionally, PYCR1 overexpression in GC tissues was linked to adverse clinical outcomes. The depletion of PYCR1 in GC cells resulted in a pronounced reduction in proliferation, the induction of apoptosis, and the attenuation of invasion and metastasis. Conversely, its ectopic expression notably augmented proliferation, restricted apoptosis, and stimulated invasion and metastasis. In addition, the knockdown of PYCR1 resulted in a significant elevation in the activation of caspase 3, a key protein involved in apoptosis. This depletion also led to a decrease in the activation or expression of proteins associated with metastasis, such as phosphorylated (p)-phosphatidylinositol 3-kinase (PI3K), p-AKT serine/threonine kinase (AKT), and snail family transcriptional repressor 1 (Snail). Additionally, it resulted in an upregulation of E-cadherin expression. Conversely, the overexpression of PYCR1 notably increased the levels of p-PI3K, p-AKT, and Snail, while simultaneously reducing E-cadherin expression.ConclusionPYCR1, by activating PI3K/AKT signaling, assumes a crucial role in governing malignant characteristics of GC cells, including proliferation, apoptosis, and metastasis. These findings underscore the promising potential of PYCR1 as a diagnostic biomarker and a target for tailored therapeutic interventions in patients with GC.

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(S)-crizotinib reduces gastric cancer growth through oxidative DNA damage and triggers pro-survival akt signal.

Publications

(S)-crizotinib reduces gastric cancer growth through oxidative DNA damage and triggers pro-survival akt signal.

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