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Molecular Biology Reports Jun 2021The constitutive activation of STAT3 through receptor tyrosine kinases triggered breast cancer cell growth and invasion-metastasis. Atiprimod impacts anti-proliferative,...
PURPOSE
The constitutive activation of STAT3 through receptor tyrosine kinases triggered breast cancer cell growth and invasion-metastasis. Atiprimod impacts anti-proliferative, anti-carcinogenic effects in hepatocellular carcinoma, lymphoma, multiple myeloma via hindering the biological activity of STAT3. Dose-dependent atiprimod evokes first autophagy as a survival mechanism and then apoptosis due to prolonged ER stress in pituitary adenoma cells. The therapeutic efficiency and mechanistic action of atiprimod in breast cancer cells have not been investigated yet. Thus, we aimed to modulate the pivotal role of ER stress in atiprimod-triggered apoptosis in MDA-MB-231 and MDA-MB-468 breast cancer cells.
RESULTS
Dose- and time-dependent atiprimod treatment inhibits cell viability and colony formation in MDA-MB-468 and MDA-MB-231 breast cancer cells. A moderate dose of atiprimod (2 μM) inhibited STAT3 phosphorylation at Tyr705 residue and also suppressed the total expression level of p65. In addition, nuclear localization of STAT1, 3, and NF-κB was prevented by atiprimod exposure in MDA-MB-231 and MDA-MB-468 cells. Atiprimod evokes PERK, BiP, ATF-4, CHOP upregulation, and PERK (Thr980), eIF2α (Ser51) phosphorylation's. However, atiprimod suppressed IRE1α-mediated Atg-3, 5, 7, 12 protein expressions and no alteration was observed on Beclin-1, p62 expression levels. PERK/eIF2α/ATF4/CHOP axis pivotal role in atiprimod-mediated G1/S arrest and apoptosis via Bak, Bax, Bim, and PUMA upregulation in MDA-MB-468 cells. Moreover, atiprimod renders MDA-MB-231 more vulnerable to type I programmed cell death by plasmid-mediated increased STAT3 expression.
CONCLUSION
Atiprimod induced prolonged ER stress-mediated apoptosis via both activating PERK/eIF2α/ATF4/CHOP axis and suppressing STAT3/NF-κB transcription factors nuclear migration in TBNC cells.
Topics: Activating Transcription Factor 4; Apoptosis; Autophagy; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Female; Humans; NF-kappa B; Reactive Oxygen Species; STAT Transcription Factors; STAT3 Transcription Factor; Spiro Compounds; Transcription Factor CHOP; eIF-2 Kinase
PubMed: 34244887
DOI: 10.1007/s11033-021-06528-1 -
Journal of Cellular Biochemistry Dec 2019Pituitary adenoma is the most common tumor with a high recurrence rate due to a hormone-dependent JAK/signal transducer and activator of transcriptions (STAT) signaling....
Pituitary adenoma is the most common tumor with a high recurrence rate due to a hormone-dependent JAK/signal transducer and activator of transcriptions (STAT) signaling. Atiprimod, a novel compound belonging to the azaspirane class of cationic amphiphilic drugs, has antiproliferative, anticarcinogenic effects in multiple myeloma, breast, and hepatocellular carcinoma by blocking STAT3 activation. Therapeutic agents' efficiency depends on endoplasmic reticulum (ER) stress-autophagy regulation during drug-mediated apoptotic cell death decision. However, the molecular machinery of dose-dependent atiprimod treatment regarding ER stress-autophagy has not been investigated yet. Thus, our aim is to investigate the ER stress-autophagy axis in atiprimod-mediated apoptotic cell death in GH-secreting rat cell line (GH3) pituitary adenoma cells. Dose-dependent atiprimod treatment decreased GH3 cell viability, inhibited cell growth, and colony formation. Upregulation of Atg5, Atg12, Beclin-1 expressions, cleavage of LC-3II and formation of autophagy vacuoles were determined only after 1 µM atiprimod exposure. In addition, atiprimod-triggered ER stress was evaluated by BiP, C/EBP-homologous protein (CHOP), p-PERK upregulation, and Ca release after 1 µM atiprimod exposure. Concomitantly, increasing concentration of atiprimod induced caspase-dependent apoptotic cell death via modulating Bcl family members. Moreover, by N-acetyl cycteinc pretreatment, atiprimod triggered reactive oxygen species generation and prevented apoptotic induction. Concomitantly, dose-dependent atiprimod treatment decreased both GH and STAT3 expression in GH3 cells. In addition, overexpression of STAT3 increased atiprimod-mediated cell viability loss and apoptotic cell death through suppressing autophagy and ER stress key molecules expression profile. In conclusion, a low dose of atiprimod exposure triggers autophagy and mild-ER stress as a survival mechanism, but increased atiprimod dose induced caspase-dependent apoptotic cell death by targeting STAT3 in GH3 pituitary adenoma cells.
Topics: Adenoma; Animals; Apoptosis; Autophagy; Calcium; Cell Cycle Checkpoints; Cell Line, Tumor; Dose-Response Relationship, Drug; Endoplasmic Reticulum Stress; Pituitary Neoplasms; Proto-Oncogene Proteins c-bcl-2; Rats; Reactive Oxygen Species; STAT3 Transcription Factor; Spiro Compounds; Transcription Factor CHOP
PubMed: 31270852
DOI: 10.1002/jcb.29281 -
Molecular Biology Reports Nov 2020Active growth hormone (GH) signaling triggers cellular growth and invasion-metastasis in colon, breast, and prostate cancer. Curcumin, an inhibitor of NF-ҡB pathway, is...
Active growth hormone (GH) signaling triggers cellular growth and invasion-metastasis in colon, breast, and prostate cancer. Curcumin, an inhibitor of NF-ҡB pathway, is assumed to be a promising anti-carcinogenic agent. Atiprimod is also an anti-inflammatory, anti-carcinogenic agent that induces apoptotic cell death in hepatocellular carcinoma, multiple myeloma, and pituitary adenoma. We aimed to demonstrate the potential additional effect of atiprimod on curcumin-induced apoptotic cell death via cytokine expression profiles in MCF-7 and MDA-MB-231 cells with active GH signaling. The effect of curcumin and/or atiprimod on IL-2, IL-4, and IL-17A levels were measured by ELISA assay. MTT cell viability, trypan blue exclusion, and colony formation assays were performed to determine the effect of combined drug exposure on cell viability, growth, and colony formation, respectively. Alteration of the NF-ҡB signaling pathway protein expression profile was determined following curcumin and/or atiprimod exposure by RT-PCR and immunoblotting. Finally, the effect of curcumin with/without atiprimod treatment on Reactive Oxygen Species (ROS) generation and apoptotic cell death was examined by DCFH-DA and Annexin V/PI FACS flow analysis, respectively. Autocrine GH-mediated IL-6, IL-8, IL-10 expressions were downregulated by curcumin treatment. Atiprimod co-treatment increased the inhibitory effect of curcumin on cell viability, proliferation and also increased the curcumin-triggered ROS generation in each GH breast cancer cells. Combined drug exposure increased apoptotic cell death through acting on IL-2, IL-4, and IL-17A secretion. Forced GH-triggered curcumin resistance might be overwhelmed by atiprimod and curcumin co-treatment via modulating NF-ҡB-mediated inflammatory cytokine expression in MCF-7 and MDA-MB-231 cells.
Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Proliferation; Cell Survival; Curcumin; Cytokines; Female; Human Growth Hormone; Humans; MCF-7 Cells; Spiro Compounds
PubMed: 33130987
DOI: 10.1007/s11033-020-05928-z