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Mol Ther. 2018 Aug 1;26(8):2019-2033. doi: 10.1016/j.ymthe.2018.05.026. Epub 2018 Jun 30.

RTN4 Knockdown Dysregulates the AKT Pathway, Destabilizes the Cytoskeleton, and Enhances Paclitaxel-Induced Cytotoxicity in Cancers.

Author information

1
Department of Pathology, Dalhousie University, Halifax, NS B3H 1X5, Canada.
2
Division of Medical Oncology, Genitourinary Cancer Program, University of Colorado School of Medicine, Aurora, CO 80045, USA.
3
Department of Pathology, Dalhousie University, Halifax, NS B3H 1X5, Canada; Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 1X5, Canada; Department of Biology, Dalhousie University, Halifax, NS B3H 1X5, Canada; Centre for Innovative and Collaborative Health Systems Research, IWK Health Centre, Halifax, NS B3K 6R8, Canada. Electronic address: shashi.gujar@dal.ca.

Abstract

Reticulon-4 (RTN4), commonly known as a neurite outgrowth inhibitor (Nogo), is emerging as an important player in human cancers. Clinically, we found lower RTN4 expression in patient-derived tumors was associated with significantly better survival in lung, breast, cervical, and renal cancer patients. To identify the role of RTN4 in cancer biology, we performed mass spectrometry-based quantitative proteomic analysis on cancer cells following RTN4 knockdown and found its link with pro-survival as well as cytoskeleton-related processes. Subsequent mechanistic investigations revealed that RTN4 regulates lipid homeostasis, AKT signaling, and cytoskeleton modulation. In particular, downregulation of RTN4 reduced sphingomyelin synthesis and impaired plasma membrane localization of AKT, wherein AKT phosphorylation, involved in many cancers, was significantly reduced without any comparable effect on AKT-related upstream kinases, in a sphingolipid-dependent manner. Furthermore, knockdown of RTN4 retarded proliferation of cancer cells in vitro as well as tumor xenografts in mice. Finally, RTN4 knockdown affected tubulin stability and promoted higher cytotoxic effects with chemotherapeutic paclitaxel in cancer cells both in vitro and in vivo. In summary, RTN4 is involved in carcinogenesis and represents a molecular candidate that may be targeted to achieve desired antitumor effects in clinics.

KEYWORDS:

Nogo; Reticulon-4; chemotherapy resistance; cytoskeleton; sphingomyelin; tumorigenesis

PMID:
30078441
PMCID:
PMC6094397
DOI:
10.1016/j.ymthe.2018.05.026
[Indexed for MEDLINE]
Free PMC Article

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