Astemizole-Histamine induces Beclin-1-independent autophagy by targeting p53-dependent crosstalk between autophagy and apoptosis

Rekha Jakhar, Souren Paul, Monika Bhardwaj, Sun Chul Kang

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Apoptosis and autophagy are genetically regulated, evolutionarily conserved processes that can jointly seal cancer cell fates, and numerous death stimuli are capable of activating either pathway. Although crosstalk between apoptosis and autophagy is quite complex and sometimes contradictory, it remains a key factor determining the outcomes of death-related pathologies such as cancer. In the present study, exposure of MCF-breast cancer cells to HIS and the H1 receptor antagonist AST both alone and together with HIS (AST-HIS) led to generation of intracellular ROS, which induced massive cellular vacuolization through dilation of the ER and mitochondria. Consequently, apoptosis by Bax translocation, cytochrome c release, and caspase activation were triggered. In addition, AST-HIS caused ER stress-induced autophagy in MCF-cells, as evidenced by an increased LC3-II/LC3-ratio, with surprisingly no changes in Beclin-expression. Non-canonical autophagy was induced via p53 phosphorylation, which increased p53-p62 interactions to enhance Beclin-1-independent autophagy as evidenced by immunocytochemistry and immunoprecipitation. In the absence of Beclin-1, enhanced autophagy further activated apoptosis through caspase induction. In conclusion, these findings indicate that AST-HIS-induced apoptosis and autophagy can be regulated by ROS-mediated signaling pathways.

Original languageEnglish (US)
Pages (from-to)89-100
Number of pages12
JournalCancer Letters
Volume372
Issue number1
DOIs
StatePublished - Mar 1 2016
Externally publishedYes

Bibliographical note

Funding Information:
Furthermore, MCF-7 cells were found to elicit ER stress-mediated autophagy via IRE1α-induced JNK and p38 activation in response to AST–HIS treatment. Our hypothesis that autophagy is induced during ER stress is supported by the following points. First, all ER stressors we examined activated autophagosome formation, as determined by AO staining and LC3 puncta formation via modulation of p62. Second, LC3 was converted from LC3-I to LC3-II in response to ER stress. Third, ER stress can stimulate proteosomal degradation of the cytosolic tumor suppressor p53, resulting in autophagy [49] .

Publisher Copyright:
© 2015 Elsevier Ireland Ltd.

Keywords

  • Apoptosis
  • Astemizole
  • ER stress
  • H1 receptor
  • Non-canonical autophagy
  • P53

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