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ABSTRACT
The inhibition of the unfolded protein response (UPR), which usually protects cancer cells from stress, may be exploited to potentiate the cytotoxic effect of drugs inducing ER stress. However, in this study, we found that ER stress and UPR activation by thapsigargin or tunicamycin promoted the lysosomal degradation of mutant (MUT) TP53 and that the inhibition of the UPR sensor ATF6, but not of ERN1/IRE1 or EIF2AK3/PERK, counteracted such an effect. ATF6 activation was indeed required to sustain the function of lysosomes, enabling the execution of chaperone-mediated autophagy (CMA) as well as of macroautophagy, processes involved in the degradation of MUT TP53 in stressed cancer cells. At the molecular level, by pharmacological and genetic approaches, we demonstrated that the inhibition of ATF6 correlated with the activation of MTOR and with TFEB and LAMP1 downregulation in thapsigargin-treated MUT TP53 carrying cells. We hypothesize that the rescue of MUT TP53 expression by ATF6 inhibition, could further activate MTOR and maintain lysosomal dysfunction, further inhibiting MUT TP53 degradation, in a vicious circle. The findings of this study suggest that the presence of MUT TP53, which often exerts oncogenic properties, should be considered before approaching treatments combining ER stressors with ATF6 inhibitors against cancer cells, while it could represent a promising strategy against cancer cells that harbor WT TP53.
Acknowledgements
We thank Francesca Chiara Ragone for technical assistance.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Abbreviations
| 3-MA | = | 3-methyladenine |
| ACTB | = | actin beta |
| AO | = | acridine orange |
| ATF6 | = | activating transcription factor 6 |
| ATG5 | = | autophagy related 5 |
| BIRC5 | = | baculoviral IAP repeat containing 5 |
| BZ | = | bortezomib |
| CHEK1 | = | checkpoint kinase 1 |
| CMA | = | chaperone-mediated autophagy |
| CRC | = | colorectal cancer; DDIT3 |
| DNA | = | damage inducible transcript 3 |
| EIF2A | = | eukaryotic translation initiation factor 2A |
| EIF2AK3 | = | eukaryotic translation initiation factor 2 alpha kinase 3 |
| EIF4EBP1 | = | eukaryotic translation initiation factor 4E binding protein 1 |
| ER | = | endoplasmic reticulum |
| ERN1 | = | endoplasmic reticulum to nucleus signaling 1 |
| GAPDH | = | glyceraldehyde-3-phosphate dehydrogenase |
| HSPA5 | = | heat shock protein family A (Hsp70) member 5 |
| HSPA8 | = | heat shock protein family A (Hsp70) member 8 |
| LAMP1 | = | lysosomal associated membrane protein 1 |
| LAMP2A | = | lysosomal associated membrane protein 2A |
| MAP1LC3B | = | microtubule associated protein 1 light chain 3 beta |
| MAP2K4 | = | mitogen-activated protein kinase kinase 4 |
| MAPT | = | microtubule associated protein tau |
| MTOR | = | mechanistic target of rapamycin kinase |
| PARP1 | = | poly(ADP-ribose) polymerase 1 |
| RPS6KB1 | = | ribosomal protein S6 kinase B1 |
| SQSTM1 | = | sequestosome 1 |
| TFEB | = | transcription factor EB |
| TG | = | thapsigargin |
| TN | = | tunicamycin |
| TP53 | = | tumor protein p53 |
| UPR | = | unfolded protein response |
| XBP1 | = | X-box binding protein 1 |
Data availability statement
Research data are stored in an institutional repository and will be shared upon reasonable request to the corresponding author.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/15548627.2024.2338577