Role and mechanism of autophagy‐regulating factors in tumorigenesis and drug resistance

Abstract

A hallmark feature of tumorigenesis is uncontrolled cell division. Autophagy is regulated by more than 30 genes and it is one of several mechanisms by which cells maintain homeostasis. Autophagy promotes cancer progression and drug resistance. Several genes play important roles in autophagy‐induced tumorigenesis and drug resistance including Beclin‐1, MIF, HMGB1, p53, PTEN, p62, RAC3, SRC3, NF‐2, MEG3, LAPTM4B, mTOR, BRAF and c‐MYC. These genes alter cell growth, cellular microenvironment and cell division. Mechanisms involved in tumorigenesis and drug resistance include microdeletions, genetic mutations, loss of heterozygosity, hypermethylation, microsatellite instability and translational modifications at a molecular level. Disrupted or altered autophagy has been reported in hematological malignancies like lymphoma, leukemia and myeloma as well as multiple solid organ tumors like colorectal, hepatocellular, gall bladder, pancreatic, gastric and cholangiocarcinoma among many other malignancies. In addition, defects in autophagy also play a role in drug resistance in cancers like osteosarcoma, ovarian and lung carcinomas following treatment with drugs such as doxorubicin, paclitaxel, cisplatin, gemcitabine and etoposide. Therapeutic approaches that modulate autophagy are a novel future direction for cancer drug development that may help to prevent issues with disease progression and overcome drug resistance.

Qiyusanlong Formula Induces Autophagy in Non-Small-Cell Lung Cancer Cells and Xenografts through the mTOR Signaling Pathway

“…As a tumor suppressor gene, Beclin-1 is a crucial modifier of autophagy and is involved in the activation of autophagy and the formation of autophagosomes [29][30][31]. LC3 and p62, the key proteins in autophagosome formation, are commonly used as autophagic markers [32]; p62 can be recruited to the autophagosomal membrane through binds interaction with LC3 [33].…”

“…mTOR is a key regulatory factor in the initiation stages of autophagy and functions as a negative regulatory molecule of autophagy, so that its activation inhibits autophagy [45]. mTOR divided into two distinct multiprotein complexes, namely mTORC1 and mTORC2, with autophagy being mainly controlled by mTORC1 [31]. Research has shown that inhibition of mTORC1 increases autophagy, while the activation of mTORC1 reduces autophagy [46].…”

The Tobacco Metabolite NNK Enhances Pancreatic Cancer Cell Stemness and Chemoresistance by Activating the β2AR-Akt Autophagy Axis

“…Cancer stem cells(CSCs) are closely related to the generation of drug resistance, their self-renewal function, formation/maintenance of the CSCs phenotype and cytoprotective machinery, allowing CSCs to survive after drug exposure [22] . Moreover, autophagy has been shown to play an important role in many biological properties of pancreatic cancer cells, including survival, dormancy and epithelial-mesenchymal transition(EMT), metastasis, and gemcitabine resistance [23] . However, the relationship between NNK, autophagy, stemness, and gemcitabine resistance in pancreatic cancer remains unclear.…”

The Contribution of Autophagy and LncRNAs to MYC-Driven Gene Regulatory Networks in Cancers

“…This structure is then fused with lysosomes, allowing for the degradation of its content. MYC, along with other genes such as mTOR, Beclin-1, p53, PTEN, p62, MIF, HMGB1, RAC3, SRC3, NF-2, MEG3, LAPTM4B, and BRAF play essential roles in autophagy-induced tumourigenesis and drug resistance, a new focus of drug development efforts [68]. Toh and colleagues showed that MYC was involved in autophagosome formation in the early stages of autophagy rather than in its degradation and that MYC-driven modulation of autophagy occurs via the JNK1-Bcl2 pathway and ROS (Figure 4).…”