Dual Akt and Bcl-2 inhibition induces cell-type specific modulation of apoptotic and autophagic signaling in castration resistant prostate cancer cell lines.

Abstract

BACKGROUND:

Cancer cell survival depends on the cross-regulation between apoptosis and autophagy which share common signaling pathways including PI3K/Akt/mTOR and Bcl-2. The aim of this study was to elucidate the modulation patterns between apoptosis and autophagy following dual inhibition by Akt inhibitor erufosine and Bcl-2 inhibitor ABT-737 in castration-resistant prostate cancer (CRPC) cell lines, PC-3 (Bax+) and DU-145 (Bax-).

METHODS AND RESULTS:

Cell cycle progression, apoptotic and autophagic signaling were examined by flow cytometry, multi-caspase assay, Hoechst staining, acridine orange staining of acidic vesicular organelles (AVOs), qRT-PCR and Western Blot. Dual inhibition increased G2/M arrest in PC-3 and DU-145, but not in the healthy prostate epithelium cells, PNT-1A. Only in PC-3, dual inhibition induced synergistic apoptotic and additive autophagic effects. In DU-145 and PNT-1A cells, ABT-737 did not display any remarkable effect on multicaspase activity and erufosine and ABT-737, neither alone nor in combination induced AVOs. By dual inhibition, AKT, BCL-2 and NF-κB gene expressions were downregulated in PC-3, both ATG-5 and BECLIN-1 gene expressions were upregulated in DU-145 but Beclin-1 protein expression was substantially reduced in both CRPC cells. Dual inhibition-induced synergistic multicaspase activation in PC-3 degrades and disrupts autophagic activity of Beclin-1, enhancing caspase-dependent apoptosis. However, in DU-145, following dual inhibition, rate of multicaspase induction and apoptosis are lower but autophagy is completely abolished despite markedly increased BECLIN-1 gene expression.

CONCLUSION:

In conclusion, antineoplastic drug combinations may display cell-type specific modulation of apoptotic and autophagic signaling and lack of protective autophagy may not necessarily indicate increased chemotherapeutic sensitivity in heterogenous tumor subpopulations.

• Authors: Ezgi Avsar Abdik, Hüseyin Abdik, Duygu Turan, Fikrettin Sahin, Martin R Berger, Ferda Kaleagasioglu
• Journal: Molecular biology reports (Mol Biol Rep) Vol. 48 Issue 12 Pg. 7755-7765 (Dec 2021) ISSN: 1573-4978 [Electronic] Netherlands
• PMID: 34647221 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature B.V.

Chemical References

• ABT-737
• Antineoplastic Agents
• BCL2 protein, human
• Biphenyl Compounds
• Nitrophenols
• Organophosphates
• Piperazines
• Proto-Oncogene Proteins c-bcl-2
• Quaternary Ammonium Compounds
• Sulfonamides
• erucylphospho-N,N,N-trimethylpropylammonium
• Proto-Oncogene Proteins c-akt

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Biphenyl Compounds (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Humans
• Male
• Nitrophenols (pharmacology)
• Organophosphates (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Piperazines (pharmacology)
• Prostatic Neoplasms, Castration-Resistant (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Quaternary Ammonium Compounds (pharmacology)
• Signal Transduction (drug effects)
• Sulfonamides (pharmacology)