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

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.

Hsa_circ_0010235 functions as an oncogenic drive in non-small cell lung cancer by modulating miR-433-3p/TIPRL axis

“…Former literature testified that TIPRL deficiency promoted the apoptosis of lung cancer H1299 cells disposed by cisplatin, suggesting its important role in lung cancer [ 35 ]. TIPRL expression was increased in NSCLC tissues in comparison to normal tissues, and TIPRL could contribute to autophagy so as to facilitate NSCLC development through the eukaryotic initiation factor 2α (eIF2α)-Activating Transcription Factor 4 (ATF4) pathway [ 23 ]. In addition, TIPRL was found to correlated with lower overall survival rate of NSCLC patients; TIPRL knockdown suppressed NSCLC metastasis, indicating that TIPRL acted as an oncogene in NSCLC [ 36 ].…”

“…TIPRL was upregulated in hepatocellular carcinoma (HCC), and it could facilitate TRAIL (a potential anti-cancer agent) resistance of HCC cells [ 22 ]. In NSCLC, enforced expression of TIPRL facilitated cell autophagy, and it could serve as an ideal therapeutic target [ 23 ]. Here, TIPRL was found to have binding position with miR-433-3p, and the interaction of TIPRL with hsa_circ_0010235-mediated NSCLC progression was also explored.…”

Echinatin suppresses esophageal cancer tumor growth and invasion through inducing AKT/mTOR-dependent autophagy and apoptosis

“…Autophagy is a tightly regulated catabolic process of cellular self-digestion, in which cytoplasm, organelles, and proteins were separated into autophagosomes and then fused with lysosomes for degeneration to maintain cell renewal and homeostasis during starvation, stress, microbial invasion, and inflammation 25 . The dysregulation of autophagy is closely related to a number of diseases, including cancer, cardiovascular disease, and autoimmunity 26 , 27 . Many of the stimulators that lead to apoptosis can trigger autophagy, in which autophagy usually appeares before cell apoptosis.…”

TIPRL, a Novel Tumor Suppressor, Suppresses Cell Migration, and Invasion Through Regulating AMPK/mTOR Signaling Pathway in Gastric Cancer

“…In hepatocellular carcinoma samples and cell lines, TIPRL is overexpressed and prevents TRAIL-induced apoptosis through inactivation of MKK7-JNK signaling (12), thereby representing a potential biomarker for early liver cancer (51). In addition, TIPRL overexpression is found to induce autophagy and accelerate growth through the eIF2α-ATF4 pathway in non-small cell lung cancer (52). Given the previous reports, TIPRL is believed to be oncogenic.…”

“…To date, the role of TIPRL in cancer has been documented only in liver and lung cancer (12,51,52). In hepatocellular carcinoma samples and cell lines, TIPRL is overexpressed and prevents TRAIL-induced apoptosis through inactivation of MKK7-JNK signaling (12), thereby representing a potential biomarker for early liver cancer (51).…”