Polyamine Anabolism Promotes Chemotherapy-Induced Breast Cancer Stem Cell Enrichment.

Breast cancer patients may initially benefit from cytotoxic chemotherapy but experience treatment resistance and relapse. Chemoresistant breast cancer stem cells (BCSCs) play a pivotal role in cancer recurrence and metastasis, however, identification and eradication of BCSC population in patients are challenging. Here, an mRNA-based BCSC signature is developed using machine learning strategy to evaluate cancer stemness in primary breast cancer patient samples. Using the BCSC signature, a critical role of polyamine anabolism in the regulation of chemotherapy-induced BCSC enrichment, is elucidated. Mechanistically, two key polyamine anabolic enzymes, ODC1 and SRM, are directly activated by transcription factor HIF-1 in response to chemotherapy. Genetic inhibition of HIF-1-controlled polyamine anabolism blocks chemotherapy-induced BCSC enrichment in vitro and in xenograft mice. A novel specific HIF-1 inhibitor britannin is identified through a natural compound library screening, and demonstrate that coadministration of britannin efficiently inhibits chemotherapy-induced HIF-1 transcriptional activity, ODC1 and SRM expression, polyamine levels, and BCSC enrichment in vitro and in xenograft and autochthonous mouse models. The findings demonstrate the key role of polyamine anabolism in BCSC regulation and provide a new strategy for breast cancer treatment.

Physiological and molecular response and tolerance of Macleaya cordata to lead toxicity.

BACKGROUND: Macleaya cordata is a traditional medicinal herb, and it has high tolerance and accumulation ability to heavy metals, which make it a good candidate species for studying phytoremediation. The objectives of this study were to investigate response and tolerance of M. cordata to lead (Pb) toxicity based on comparative analysis of transcriptome and proteome. RESULTS: In this study, the seedlings of M. cordata cultured in Hoagland solution were treated with 100 µmol·L- 1 Pb for 1 day (Pb 1d) or 7 days (Pb 7d), subsequently leaves of M. cordata were taken for the determination of Pb accumulation and hydrogen peroxide production (H2O2), meanwhile a total number of 223 significantly differentially expressed genes (DEGs) and 296 differentially expressed proteins (DEPs) were screened between control and Pb treatments. The results showed leaves of M. cordata had a special mechanism to maintain Pb at an appropriate level. Firstly, some DEGs were iron (Fe) deficiency-induced transporters, for example, genes of vacuolar iron transporter and three ABC transporter I family numbers were upregulated by Pb, which can maintain Fe homeostasis in cytoplasm or chloroplast. In addition, five genes of calcium (Ca2+) binding proteins were downregulated in Pb 1d, which may regulate cytoplasmic Ca2+ concentration and H2O2 signaling pathway. On the other hand, the cysteine synthase upregulated, glutathione S-transferase downregulated and glutathione reductase downregulated in Pb 7d can cause reduced glutathione accumulation and decrease Pb detoxification in leaves. Furthermore, DEPs of eight chlorophyll a/b binding proteins, five ATPases and eight ribosomal proteins can play a pivotal role on chloroplast turnover and ATP metabolism. CONCLUSIONS: Our results suggest that the proteins involved in Fe homeostasis and chloroplast turnover in mesophyll cells may play key roles in tolerance of M. cordata to Pb. This study offers some novel insights into Pb tolerance mechanism of plants, and the potential valuable for environmental remediation of this important medicinal plant.

Conjugated/nonconjugated alternating copolymers for enhanced NIR-II fluorescence imaging and NIR-II photothermal-ferrotherapy.

Conjugated polymers hold great promise for NIR-II fluorescence imaging (FI)-guided NIR-II photothermal therapy (PTT) due to the advantages of easy modification of chemical structures and adjustable NIR absorption. However, to make use of these advantages, it is of paramount importance to formulate conjugated polymers with excellent solubility in organic solution, great NIR-II photothermal conversion efficiency, and high NIR-II fluorescence quantum yield. Herein, a new class of conjugated/nonconjugated alternating copolymers (CNACPs) is reported by introducing nonconjugated linkers into a conjugated backbone to modulate the extinction coefficient at 1064 nm and NIR-II fluorescence quantum yield. The NIR-II absorption, NIR-II emission, and NIR-II photothermal properties of the new CNACPs were studied. Interestingly, it is observed that longer nonconjugated linkers in CNACPs result in higher NIR-II fluorescence intensity with sufficient NIR-II absorption and NIR-II photothermal ability. With these newly developed CNACPs (BBT-C6), phototheranostic nanoparticles (BBTD6/Fe@PMA) are prepared through facile nanoprecipitation using PMA-AD-PEG as an iron ion chelator for NIR-II FI-guided NIR-II PTT/ferrotherapy synergistic therapy. In vitro and in vivo, BBTD6/Fe@PMA effectively inhibited 4T1 cells and tumor progression under 1064 nm laser irradiation. Consequently, this work provides new CNACPs by incorporating nonconjugated linkers into a conjugated backbone to design more effective NIR-II fluorescence imaging and NIR-II photothermal therapy agents.