PAWR-mediated suppression of BCL2 promotes switching of 3-azido withaferin A (3-AWA)-induced autophagy to apoptosis in prostate cancer cells
| Autor: | Lekha Dinesh Kumar, Debaraj Mukherjee, Reyaz ur Rasool, Debasis Nayak, Bilal Rah, Syed Khalid Yousuf, Anindya Goswami |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
PAWR Apoptosis Basic Science Research Papers Biology chemistry.chemical_compound Prostate cancer Cell Line Tumor medicine Autophagy Humans Molecular Biology Endoplasmic Reticulum Chaperone BiP Withanolides Prostatic Neoplasms Cell Biology BECN1 medicine.disease Endoplasmic Reticulum Stress chemistry Proto-Oncogene Proteins c-bcl-2 Withaferin A Unfolded protein response Cancer research Apoptosis Regulatory Proteins MAP1LC3B Signal Transduction |
| Popis: | An active medicinal component of plant origin with an ability to overcome autophagy by inducing apoptosis should be considered a therapeutically active lead pharmacophore to control malignancies. In this report, we studied the effect of concentration-dependent 3-AWA (3-azido withaferin A) sensitization to androgen-independent prostate cancer (CaP) cells which resulted in a distinct switching of 2 interrelated conserved biological processes, i.e. autophagy and apoptosis. We have observed 3 distinct parameters which are hallmarks of autophagy in our studies. First, a subtoxic concentration of 3-AWA resulted in an autophagic phenotype with an elevation of autophagy markers in prostate cancer cells. This led to a massive accumulation of MAP1LC3B and EGFP-LC3B puncta coupled with gradual degradation of SQSTM1. Second, higher toxic concentrations of 3-AWA stimulated ER stress in CaP cells to turn on apoptosis within 12 h by elevating the expression of the proapoptotic protein PAWR, which in turn suppressed the autophagy-related proteins BCL2 and BECN1. This inhibition of BECN1 in CaP cells, leading to the disruption of the BCL2-BECN1 interaction by overexpressed PAWR has not been reported so far. Third, we provide evidence that pawr-KO MEFs exhibited abundant autophagy signs even at toxic concentrations of 3-AWA underscoring the relevance of PAWR in switching of autophagy to apoptosis. Last but not least, overexpression of EGFP-LC3B and DS-Red-BECN1 revealed a delayed apoptosis turnover at a higher concentration of 3-AWA in CaP cells. In summary, this study provides evidence that 3-AWA is a strong anticancer candidate to abrogate protective autophagy. It also enhanced chemosensitivity by sensitizing prostate cancer cells to apoptosis through induction of PAWR endorsing its therapeutic potential. |
| Databáze: | OpenAIRE |
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