Inhibiting autophagy before it starts.

ABSTRACT

Autophagy, an important cellular stress response mechanism, is often exploited by a variety of cancer cells to sustain rapid growth under stresses such as nutrient deprivation and hypoxia. Autophagy also plays a key role in tumor resistance to chemotherapy, radiotherapy or targeted therapy. Inhibition of autophagy is therefore a promising tumor treatment strategy. However, there is still a lack of effective autophagy inhibitors suitable for clinical use. Most drug development has focused on enzymes like the VPS34 and ULK1 kinases, or the cysteine protease ATG4B, which plays different roles in autophagy. We discovered a drug molecule Eltrombopag that inhibits the expression of autophagic lysosomal genes at the stage of transcriptional level, where the synthesis of these proteins has not really begun, by directly inhibiting the TFEB (transcription factor EB). This drug can improve the therapeutic effect of Temozolomide on glioblastoma treatment, further confirming the value of inhibiting autophagy in the treatment of cancer.Abbreviation VPS34 vacuolar protein sorting 34; ULK1 unc-51 like autophagy activating kinase 1; TFEB transcription factor EB; MITF microphthalmia-associated transcription factor; TFE3 transcription factor E3; EO Eltrombopag; ITC isothermal titration calorimetry; bHLH-LZ basic helix-loop-helix leucine zipper; LAMP1 lysosomal-associated membrane protein 1; CTSF cathepsin F; HEXA hexosaminidase subunit alpha.