4955 - XAF1 Enhances Temozolomide Induced Autophagic Cell Death through AMPK signaling pathway

Background

XIAP-associated factor 1 (XAF1) is a pro-apoptotic tumor suppressor whose expression is inactivated in many human malignancies. To explore the XAF1’s candidacy for a suppressor in the pathogenesis of human glioma, we investigated its expression and function in tumor cell lines and tissues.

Methods

Expression study was performed using quantitative RT-PCR and immunoblot assays. Functional interplay between XAF1 and AMPK was determined by gene transfection, siRNA-mediated depletion.

Results

XIAP-associated factor 1 (XAF1) is a pro-apoptotic tumor suppressor whose expression is inactivated in many human malignancies. In this study, we explored the XAF1’s candidacy for a suppressor in human glioma pathogenesis. XAF1 reduction is more common in high grade tumors versus low grade tumors and tightly associated with aberrant hypermethylation at 7 CpG sites in the 5’ proximal region of the promoter. XAF1 expression decreases proliferation and colony-forming ability of glioma cells while its depletion enhances cellular resistance to genotoxic drugs, such as temozolomide (TMZ), etoposide and cisplatin. The XAF1 promoter is activated in response to TMZ through JNK-IRF-1 signaling and its activation greatly increases cellular response to TMZ-induced cell death. Furthermore, XAF1 promotes autophagic cell death (ACD) by activating AMP-activated protein kinase (AMPK) in a XIAP-independent manner. Both AMPK-activating and ACD-inducing effects of XAF1 are linked to its activity to decrease intracellular ATP level, oxygen consumption, and mitochondrial membrane potential. XAF1 proteins translocate to the mitochondria and the zinc finger (ZF) 6 domain is essential for its mitochondrial distribution. Consistently, a mutant XAF1 lacking the ZF6 fails to decrease ATP level, activate AMPK, and trigger AMPK-mediated autophagic cell death. Collectively, this study demonstrates that epigenetic inactivation of XAF1 contributes to the malignant progression of human glioma by rendering tumor cells a survival advantage via the attenuation of AMPK signaling.

Conclusions

Epigenetic inactivation of XAF1 contributes to the malignant progression of human glioma by rendering tumor cells a survival advantage via the attenuation of AMPK signaling.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2018R1D1A1B07041512).

Disclosure

All authors have declared no conflicts of interest.