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TIPRL potentiates survival of lung cancer by inducing autophagy through the eIF2α-ATF4 pathway
- Source :
- Cell Death & Disease, Cell Death and Disease, Vol 10, Iss 12, Pp 1-17 (2019)
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
Abstract
- Autophagy, an intracellular system of degrading damaged organelles and misfolded proteins, is essential for cancer cell survival. Despite the progress made towards understanding the mechanism, identification of novel autophagy regulators presents a major obstacle in developing anticancer therapies. Here, we examine the association between the TOR signaling pathway regulator-like (TIPRL) protein and autophagy in malignant transformation of tumors. We show that TIPRL upregulation in non-small cell lung cancer (NSCLC) potentiated autophagy activity and enabled autophagic clearance of metabolic and cellular stress, conferring a survival advantage to cancer cells. Importantly, the interaction of TIPRL with eukaryotic initiation factor 2α (eIF2α) led to eIF2α phosphorylation and activation of the eIF2α-ATF4 pathway, thereby inducing autophagy. Conversely, TIPRL depletion increased apoptosis by reducing autophagic clearance, which was markedly enhanced in TIPRL-depleted A549 xenografts treated with 2-deoxy-D-glucose. Overall, the study indicated that TIPRL is a potential regulator of autophagy and an important drug target for lung cancer therapy.
- Subjects :
- Male
Cancer Research
Lung Neoplasms
Cell Survival
Eukaryotic Initiation Factor-2
Immunology
Apoptosis
Biology
Article
Malignant transformation
Stress signalling
Mice
Cellular and Molecular Neuroscience
Downregulation and upregulation
Carcinoma, Non-Small-Cell Lung
Spheroids, Cellular
Eukaryotic initiation factor
Autophagy
Animals
Humans
lcsh:QH573-671
Phosphorylation
lcsh:Cytology
ATF4
Intracellular Signaling Peptides and Proteins
Cell Biology
Endoplasmic Reticulum Stress
Activating Transcription Factor 4
A549 Cells
Cancer cell
Cancer research
Heterografts
Female
Non-small-cell lung cancer
Intracellular
Signal Transduction
Subjects
Details
- ISSN :
- 20414889
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Cell Death & Disease
- Accession number :
- edsair.doi.dedup.....00cb0e5179a2d3cdef3662f6d69d1be8
- Full Text :
- https://doi.org/10.1038/s41419-019-2190-0