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AbstractAcquired chemoresistance remains a significant challenge in the clinics as most of the treated cancers eventually emerge as hard-to-treat phenotypes. Therefore, identifying chemoresistance targets is highly warranted to manage the disease better. In this study, we employed a label-free LC-MS/MS-based quantitative proteomics analysis to identify potential targets and signaling pathways underlying acquired chemoresistance in a sub-cell line (A549DR) derived from the parental lung adenocarcinoma cells (A549) treated with gradually increasing doses of doxorubicin (DOX). Our proteomics analysis identified 146 upregulated and 129 downregulated targets in A549DR cells. The KEGG pathway and Gene ontology (GO) analysis of differentially expressed upregulated and downregulated proteins showed that most abundant upregulated pathways were related to metabolic pathways, cellular senescence, cell cycle, and p53 signaling. Meanwhile, the downregulated pathways were related to spliceosome, nucleotide metabolism, DNA replication, nucleotide excision repair, and nuclear-cytoplasmic transport. Further, STRING analysis of upregulated biological processes showed a protein-protein interaction (PPI) between CDK1, AKT2, SRC, STAT1, HDAC1, FDXR, FDX1, NPC1, ALDH2, GPx1, CDK4, and B2M, proteins. The identified proteins in this study might be the potential therapeutic targets for mitigating DOX resistance. [ABSTRACT FROM AUTHOR]

Drug repurposing holds abundant opportunity in the development of novel anticancer drugs. Chloroquine (CQ), a FDA approved anti-malarial drug, is demonstrated to enhance anticancer efficacy of standard anticancer drugs including doxorubicin (DOX) in several types of cancer cells. Here, we aimed to exploit the chemosensitizing effects of CQ against DOX in human cervical cancer (HeLa) cells that remains to be investigated yet. We show that a combination of DOX (40 nM) and CQ (40 μM) resulted in a synergistic cytotoxicity (combination index; CI < 1) in HeLa cells compared to the DOX or CQ alone. Synergistic effect of the combination (DOX + CQ) was associated with the impaired autophagic flux and enhanced apoptosis. Following treatment with the combination (DOX + CQ), the level of p62/SQSTM and LC-3II proteins was increased, while a decrease was noted in the expression of LAMP-2, Syntaxin17, Rab 5, and Rab 7 proteins that play critical roles in the fusion of autophagosomes to lysosomes. Autophagy inhibition by combination (DOX + CQ) enhanced the apoptotic cell death synergistically by increasing the cleavage of procaspase-3 and PARP1. Further, a prior incubation of HeLa cells with Z-VAD-FMK (a pan-caspase inhibitor) for 4 h, suppressed the combination (DOX + CQ)-induced cell death. Our data suggest that a combination of DOX + CQ had a better anti-cancer efficacy in HeLa cells than either of the drugs alone. Thus, CQ, as a repurposed drug, may hold the potential to synergize anticancer effects of DOX in cervical cancer cells. [Display omitted] • Chloroquine (CQ) synergizes doxorubicin (DOX) efficacy in cervical cancer cells. • A combination of DOX + CQ impairs autophagy flux severely in cervical cancer cells. • DOX + CQ targets proteins involved in the fusion of autophagosomes to the lysosomes. • DOX + CQ reduced the expression of Rab5, Rab7, Syntaxin 17, and LAMP2 synergistically. • DOX + CQ mediated autophagy impairment resulted in the caspase-3 dependent apoptosis. [ABSTRACT FROM AUTHOR]

[Display omitted] Tectona grandis L.f. (Teak), a very important source of incomparable timber, withstands a wide range of tropical deciduous conditions. We achieved partial amplification of pectin methylesterase inhibitor 51 (PMEI) gene in teak by E. pilularis cinnamoyl Co-A reductase (CCR) gene specific primer. The amplified teak gene was of 750 bp, 79% identity and 97% query cover with PMEI of Sesamum indicum. The phylogenetic tree clustered the amplified gene with PMEI of database plant species, Erythranthe guttata and Sesamum indicum (87% bootstrap value). On conversion to amino acid sequence, the obtained protein comprised 237 amino acids. However, PMEI region spanned from 24 to 171 amino acids, 15.94 kDa molecular weight, 8.97 pI value and C 697 H 1117 N 199 O 211 S 9 molecular formula with four conserved cysteine residues as disulfide bridges. 25.9 % protein residues were hydrophilic, 42.7% hydrophobic and 31.2% neutral. Teak 3D PMEI protein structure corresponded well with Arabidopsis thaliana and Actinidia deliciosa PMEIs. The gene maintains integrity of pectin component of middle lamella of primary cell wall and confers tolerance against various kinds of stresses. Teak conferred with overexpression of PMEI may secure a wide adaptability as well as luxuriant timber productivity and quality in adverse/ fluctuating/ scarce climatic and environmental conditions of tropical forests. [ABSTRACT FROM AUTHOR]

The frequency of estrogen receptor alpha (ERα)-positive breast cancers and their metastatic progression is prevalent in females globally. Aberrant interaction of estrogen-like endocrine-disrupting chemicals (EDCs) is highly implicated in breast carcinogenesis. Studies have shown that single or acute exposures of weak EDCs such as bisphenol A (BPA) may not have a substantial pro-carcinogenic/metastatic effect. However, repeated exposure to EDCs is expected to strongly induce carcinogenic/metastatic progression, which remains to be studied. Low metastatic ERα-positive human breast cancer cells (MCF-7) were exposed to nanomolar doses of BPA every 24 h (up to 200 days) to study the effect of repeated exposure on metastatic potential. Following the designated treatment of BPA, markers of epithelial-mesenchymal transition (EMT), migration and invasion, mitochondrial biogenesis, ATP levels, and peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) knockdown assays were performed. A repeated exposure of low dose BPA induced stable epithelial-mesenchymal plasticity in MCF-7 cells to augment migration and invasion in the ERα-dependent pathway. Repeated exposures of BPA increased the levels of several mesenchymal markers such as N-cadherin, vimentin, cluster of differentiation 44 (CD44), slug, and alpha-smooth muscle actin (α-SMA), whereas reduced the level of E-cadherin drastically. BPA-induced mitochondrial biogenesis favored metastatic aggression by fulfilling bioenergetics demand via PGC-1α/NRF1/ERRα signaling. Knockdown of PGC-1α resulted in suppressing both mitochondrial biogenesis and EMT in BPA exposed MCF-7 cells. Repeated exposures of low dose BPA may induce metastatic aggression in ERα-positive breast cancer cells via PGC-1α-mediated mitochondrial biogenesis and epithelial-mesenchymal plasticity. [Display omitted] • Repeated exposures of BPA induced an irreversible epithelial-mesenchymal plasticity. • BPA-induced PGC1α/NRF-1/ERRα signaling regulated bioenergetics demand and EMT. • Targeting of PGC-1α inhibited both mitochondrial biogenesis and metastatic changes. • Long-term repeated exposure of EDCs like BPA acts as a strong metastatic inducer. [ABSTRACT FROM AUTHOR]