TIPRL potentiates survival of lung cancer by inducing autophagy through the eIF2α-ATF4 pathway

Cell Death Dis. 2019 Dec 20;10(12):959. doi: 10.1038/s41419-019-2190-0.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Activating Transcription Factor 4 / genetics*
  • Animals
  • Apoptosis
  • Autophagy / genetics
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Survival
  • Endoplasmic Reticulum Stress
  • Eukaryotic Initiation Factor-2 / genetics*
  • Female
  • Heterografts
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Phosphorylation
  • Signal Transduction
  • Spheroids, Cellular / pathology

Substances

  • ATF4 protein, human
  • EIF2S1 protein, human
  • Eukaryotic Initiation Factor-2
  • Intracellular Signaling Peptides and Proteins
  • TIPRL protein, human
  • Activating Transcription Factor 4