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.
Highlights
Autophagy promotes cancer growth and progression by alleviating metabolic stress and by enhancing the supply of nutrients via the degradation of cellular organelles and unfolded proteins[1]
TOR signaling pathway regulator-like (TIPRL) expression levels are correlated with malignancy in non-small cell lung cancer First, we examined the levels of TIPRL in clinical lung cancer specimens, and found that tumor tissues had significantly higher levels of TIPRL than normal tissues (Fig. 1a)
These results demonstrate the association between TIPRL and cancer malignancy, and suggest that an overexpression of TIPRL could potentially confer metabolic benefits to lung cancer cells, helping malignant cells to survive
Summary
Autophagy promotes cancer growth and progression by alleviating metabolic stress and by enhancing the supply of nutrients via the degradation of cellular organelles and unfolded proteins[1]. Several studies have demonstrated that autophagy can act as both a suppressor and an activator of cancer. Rao et al demonstrated that autophagy suppression promoted tumor initiation in murine lung cancer; continued suppression eventually reduced tumor masses, suggesting the essential and Autophagy is an important adaptive mechanism for cancer cells, because cancer cells demand higher metabolic and biosynthetic activities. Mitophagy has been reported to promote cancer cell survival by relieving cellular stress resulting from dysfunctional mitochondria ascribed to excess accumulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS)[3,4]. The failure of autophagy to mitigate mitochondria-originated and ER-originated stresses results in cancer cell death[7,8,9]. Cancer cells bypass the cellular checkpoints, thereby preventing cell cycle arrest
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