AT7867 Inhibits Human Colorectal Cancer Cells via AKT-Dependent and AKT-Independent Mechanisms

Zhang, Shihu; Deng, Zhangshuang; Yao, Chen; Huang, Ping; Zhang, Yi; Cao, Shibing; Li, Xiangcheng

doi:10.1371/journal.pone.0169585

Cited by 16 publications

(16 citation statements)

References 39 publications

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“…A previous study indicated that inhibition of SPHK1 activity by treatment with safingol markedly potentiated epigallocatechin gallate-induced apoptotic activity in vitro and in vivo (32). The results of the present study were consistent with several studies on other cancer types (33)(34)(35). In addition, inhibition of SPHK1 was demonstrated to sensitize TC cells to chemotherapeutic drugs, including 5-fluorouracil, docetaxel, doxorubicin and cisplatin.…”

Section: Discussionsupporting

confidence: 91%

SPHK1 promotes metastasis of thyroid carcinoma through activation of the S1P/S1PR3/Notch signaling pathway

Zhao

et al. 2018

Exp Ther Med

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Thyroid carcinoma is characterized by an aggressive behavior, lack of effective targeted therapies and a high rate of relapse. Sphingosine kinase 1 (SPHK1) has been reported to be a critical regulatory factor in the progression of thyroid carcinoma, but the correlation between SPHK1 and clinical prognosis of patients with thyroid carcinoma has remained to be fully elucidated. The present study aimed to systematically assess the roles of SPHK1 in thyroid carcinoma metastasis and further investigate the possible underlying mechanisms. First, the expression of SPHK1 was detected in tissue samples from 53 thyroid carcinoma patients and in thyroid carcinoma cell lines by reverse transcription-quantitative polymerase chain reaction analysis. Furthermore, the level of phospho-(p)-SPHK1 was immunohistochemically detected in human thyroid carcinoma tissue samples. The activity of SPHK1 was measured with a commercial SPHK1 Activity Assay kit. A sphingosine-1-phosphate (S1P) competitive ELISA kit was used to determine the extracellular S1P levels. The metastatic potential was assessed by a Transwell assay. In addition, the association between SPHK1 and clinicopathological features of the patients was analyzed. The results indicated that the expression of SPHK1 in thyroid carcinoma samples was significantly higher than in paired adjacent normal thyroid tissues. High levels of SPHK1 were positively correlated with poor overall survival and progression-free survival. Downregulation of SPHK1 by lentiviral vector expressing SPHK1 small interfering (si)RNA evidently repressed Notch signaling and reduced the migration and invasion of thyroid carcinoma cells and in a NOD/SCID mouse model. Furthermore, inhibition of SPHK1 by siRNA or treatment with SPHK1 inhibitor 5C sensitized thyroid carcinoma to cisplatin and doxorubicin. In addition, it was demonstrated that silencing of SPHK1 effectively inhibits processes associated with thyroid carcinoma metastasis through the Notch signaling pathway, and SPHK1 may therefore represent a potential therapeutic target in thyroid carcinoma. In conclusion, the present study indicated that high levels of p-SPHK1 were positively correlated with high levels of S1P which in turn promoted thyroid carcinoma metastasis via the S1P/S1P receptor 3/Notch signaling pathway, suggesting possible prognostic markers and therapeutic targets.

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Section: Discussionsupporting

confidence: 91%

SPHK1 promotes metastasis of thyroid carcinoma through activation of the S1P/S1PR3/Notch signaling pathway

Zhao

et al. 2018

Exp Ther Med

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“…As described [ 54 , 55 ], aliquots of 30 μg (per sample) tissue or cell lysates (in RIPA lysis buffer) were electro-transferred to 10-12% SDS-PAGE gel, following by transfer to PVDF membranes. The blots were blocked by 10% milk and were then incubated with designated primary and secondary antibodies.…”

Section: Methodsmentioning

confidence: 99%

“…As described [ 54 ], the female severe combined immunodeficient (SCID) mice (age 4-5 week, weight 18-19 g) were obtained from the Animal Center of Fujian Medical University (Fuzhou, China), and were housed under standard procedures. Animals were randomized into three groups.…”

Section: Methodsmentioning

confidence: 99%

Silencing protein kinase C ζ by microRNA-25-5p activates AMPK signaling and inhibits colorectal cancer cell proliferation

Zhang

Cheng

et al. 2017

Oncotarget

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Developing novel strategies against human colorectal cancer (CRC) cells is needed. Activation of AMP-activated protein kinase (AMPK) could possibly inhibit CRC cells. Protein kinase C ζ (PKCζ) is an AMPK negative regulator. Here we found that PKCζ expression was significantly elevated in human colon cancer tissues and CRC cells. PKCζ upregulation was correlated with AMPK in-activation and mTOR complex 1 (mTORC1) over-activation. Reversely, PKCζ shRNA knockdown activated AMPK signaling and inhibited HT-29 cell proliferation. Significantly, downregulation of microRNA-25-5p (miR-25-5p), a PKCζ-targeting miRNA, could be the cause of PKCζ upregulation. Exogenous expression of miR-25-5p silenced PKCζ to activate AMPK signaling, which inhibited HT-29 cell proliferation. In vivo studies showed that HT-29 xenograft growth in mice was inhibited after expressing PKCζ shRNA or miR-25-5p. Collectively, PKCζ could be a novel oncogenic protein of human CRC. PKCζ silence, by targeted-shRNA or miR-25-5p expression, activates AMPK and inhibits HT-29 cell proliferation.

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“…PI3K/Akt pathway activation is a recognized mechanism by which colorectal cancer cells resist stress-induced apoptosis (41)(42)(43). We thus sought to determine whether KP metabolites offer protection against apoptosis in colorectal cancer cells.…”

Section: Kyn Protects Colorectal Cancer Cells From Apoptosismentioning

confidence: 99%

IDO1 and Kynurenine Pathway Metabolites Activate PI3K-Akt Signaling in the Neoplastic Colon Epithelium to Promote Cancer Cell Proliferation and Inhibit Apoptosis

et al. 2019

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The tryptophan-metabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) is frequently overexpressed in epithelial-derived malignancies, where it plays a recognized role in promoting tumor immune tolerance. We previously demonstrated that the IDO1-kynurenine pathway (KP) also directly supports colorectal cancer growth by promoting activation of b-catenin and driving neoplastic growth in mice lacking intact adaptive immunity. In this study, we sought to delineate the specific role of epithelial IDO1 in colon tumorigenesis and define how IDO1 and KP metabolites interact with pivotal neoplastic signaling pathways of the colon epithelium. We generated a novel intestinal epithelial-specific IDO1 knockout mouse and utilized established colorectal cancer cell lines containing b-catenin-stabilizing mutations, human colorectal cancer samples, and human-derived epithelial organoids (colonoids and tumoroids). Mice with intestinal epithelial-specific knockout of IDO1 developed fewer and smaller tumors than wild-type littermates in a model of inflammation-driven colon tumorigenesis. Moreover, their tumors exhibited reduced nuclear b-catenin and neoplastic proliferation but increased apoptosis. Mechanistically, KP metabolites (except kynurenic acid) rapidly activated PI3K-Akt signaling in the neoplastic epithelium to promote nuclear translocation of b-catenin, cellular proliferation, and resistance to apoptosis. Together, these data define a novel cell-autonomous function and mechanism by which IDO1 activity promotes colorectal cancer progression. These findings may have implications for the rational design of new clinical trials that exploit a synergy of IDO1 inhibitors with conventional cancer therapies for which Akt activation provides resistance such as radiation.Significance: This study identifies a new mechanistic link between IDO1 activity and PI3K/AKT signaling, both of which are important pathways involved in cancer growth and resistance to cancer therapy. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

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AT7867 Inhibits Human Colorectal Cancer Cells via AKT-Dependent and AKT-Independent Mechanisms

Cited by 16 publications

References 39 publications

SPHK1 promotes metastasis of thyroid carcinoma through activation of the S1P/S1PR3/Notch signaling pathway

SPHK1 promotes metastasis of thyroid carcinoma through activation of the S1P/S1PR3/Notch signaling pathway

Silencing protein kinase C ζ by microRNA-25-5p activates AMPK signaling and inhibits colorectal cancer cell proliferation

IDO1 and Kynurenine Pathway Metabolites Activate PI3K-Akt Signaling in the Neoplastic Colon Epithelium to Promote Cancer Cell Proliferation and Inhibit Apoptosis

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