Abstract
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. 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 (2μM) 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. 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.
Highlights
Breast cancer (BC) is the second cause of cancer-related death among females worldwide
MDA-MB-468 cells were more sensitive against atiprimod exposure, prolonged drug treatment overcame atiprimod resistance in MDA-MB-231 BC cells (Fig. 1a)
A moderate dose of atiprimod (2 μM) hinders the MDA-MB-468 and MDA-MB-231 cell growth, colony formation and cell migration (Fig. 1b, d, e, f). 2 μM atiprimod causes cytostatic effects on MDAMB-231 cells but the cytotoxic effect was observed in MDA-MB-468 cells after 48 h atiprimod exposure by growth assay (Fig. 1b, e)
Summary
Breast cancer (BC) is the second cause of cancer-related death among females worldwide. Underlaying molecular mechanism of BC development is associated with various hormones such as Epidermal Growth Factor (EGF), Vascular Endothelial Growth Factor (VEGF), progesterone and estrogen. Due to growth triggering signals, extracellular receptor profile of BC is correlated with aggressiveness and determines the response of BC against drug regimens [2]. Estrogen Receptor positive (ER+) expression profile and give therapeutic achievement against adjuvant anti-estrogen therapy. %10–20 of BC cases are ER- and give no significant response against hormonal or targeted therapy. Radiotherapy and chemotherapy (olaparib, Talzenna, atezolizumab) combinations preferred for ER- BCs treatment, still new therapeutic agents needed to develop for triple negative breast cancer (TNBCs) therapy [3]
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