Abstract 4373: Targeting lung cancer stem cells with inhibition of multiple drug resistance by demethoxylcurcumin-carrying chitosan-antibody core-shell nanoparticles

Despite some progress, treating advanced prostate cancer remains a major clinical challenge. Recent studies have shown that prostate cancer can originate from undifferentiated, rare, stem cell-like populations within the heterogeneous tumor mass, which play seminal roles in tumor formation, maintenance of tumor homeostasis and initiation of metastases. These cells possess enhanced propensity toward chemoresistance and may serve as a prognostic factor for prostate cancer recurrence. Despite extensive studies, selective targeted therapies against these stem cell-like populations are limited and more detailed experiments are required to develop novel targeted therapeutics. We now show that MDA-9/Syntenin/SDCBP (MDA-9) is a critical regulator of survival, stemness and chemoresistance in prostate cancer stem cells (PCSCs). MDA-9 regulates the expression of multiple stem-regulatory genes and loss of MDA-9 causes a complete collapse of the stem-regulatory network in PCSCs. Loss of MDA-9 also sensitizes PCSCs to multiple chemotherapeutics with different modes of action, such as docetaxel and trichostatin-A, suggesting that MDA-9 may regulate multiple drug resistance. Mechanistically, MDA-9-mediated multiple drug resistance, stemness and survival are regulated in PCSCs through activation of STAT3. Activated STAT3 regulates chemoresistance in PCSCs through protective autophagy as well as regulation of MDR1 on the surface of the PCSCs. We now demonstrate that MDA-9 is a critical regulator of PCSC survival and stemness via exploiting the inter-connected STAT3 and c-myc pathways.

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Targeting multiple genes containing long mononucleotide A-T repeats in lung cancer stem cells

Journal of Translational Medicine ◽

10.1186/s12967-021-02902-6 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Narumol Bhummaphan ◽

Piyapat Pin-on ◽

Preeyaporn Plaimee Phiboonchaiyanan ◽

Jirattha Siriluksana ◽

Chatchawit Aporntewan ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cell ◽

Transcriptional Control ◽

Single Gene ◽

Repeat Sequence ◽

Control Activity ◽

Multiple Genes ◽

Lung Cancer Stem Cells

Abstract Background Intratumour heterogeneous gene expression among cancer and cancer stem cells (CSCs) can cause failure of current targeted therapies because each drug aims to target the function of a single gene. Long mononucleotide A-T repeats are cis-regulatory transcriptional elements that control many genes, increasing the expression of numerous genes in various cancers, including lung cancer. Therefore, targeting A-T repeats may dysregulate many genes driving cancer development. Here, we tested a peptide nucleic acid (PNA) oligo containing a long A-repeat sequence [A(15)] to disrupt the transcriptional control of the A-T repeat in lung cancer and CSCs. Methods First, we separated CSCs from parental lung cancer cell lines. Then, we evaluated the role of A-T repeat gene regulation by counting the number of repeats in differentially regulated genes between CSCs and the parental cells of the CSCs. After testing the dosage and effect of PNA-A15 on normal and cancer cell toxicity and CSC phenotypes, we analysed genome-wide expression to identify dysregulated genes in CSCs. Results The number of A-T repeats in genes differentially regulated between CSCs and parental cells differed. PNA-A15 was toxic to lung cancer cells and CSCs but not to noncancer cells. Finally, PNA-A15 dysregulated a number of genes in lung CSCs. Conclusion PNA-A15 is a promising novel targeted therapy agent that targets the transcriptional control activity of multiple genes in lung CSCs.

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The mitochondrial fission factor FIS1 promotes stemness of human lung cancer stem cells via mitophagy

FEBS Open Bio ◽

10.1002/2211-5463.13207 ◽

2021 ◽

Author(s):

Doudou Liu ◽

Zhiwei Sun ◽

Ting Ye ◽

Jingyuan Li ◽

Bin Zeng ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Human Lung ◽

Mitochondrial Fission ◽

Human Lung Cancer ◽

Lung Cancer Stem Cells

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Lung Cancer Stem Cells—Origin, Diagnostic Techniques and Perspective for Therapies

Cancers ◽

10.3390/cancers13122996 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2996

Author(s):

Agata Raniszewska ◽

Iwona Kwiecień ◽

Elżbieta Rutkowska ◽

Piotr Rzepecki ◽

Joanna Domagała-Kulawik

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Early Recognition ◽

Human Life ◽

Clonal Evolution ◽

Diagnostic Techniques ◽

Complex Processes ◽

Age Related ◽

Lung Cancer Stem Cells

Lung cancer remains one of the most aggressive solid tumors with an overall poor prognosis. Molecular studies carried out on lung tumors during treatment have shown the phenomenon of clonal evolution, thereby promoting the occurrence of a temporal heterogeneity of the tumor. Therefore, the biology of lung cancer is interesting. Cancer stem cells (CSCs) are involved in tumor initiation and metastasis. Aging is still the most important risk factor for lung cancer development. Spontaneously occurring mutations accumulate in normal stem cells or/and progenitor cells by human life resulting in the formation of CSCs. Deepening knowledge of these complex processes and improving early recognition and markers of predictive value are of utmost importance. In this paper, we discuss the CSC hypothesis with an emphasis on age-related changes that initiate carcinogenesis. We analyze the current literature in the field, describe our own experience in CSC investigation and discuss the technical challenges with special emphasis on liquid biopsy.

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Autophagy augments the self-renewal of lung cancer stem cells by the degradation of ubiquitinated p53

Cell Death and Disease ◽

10.1038/s41419-021-03392-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jianyu Wang ◽

Doudou Liu ◽

Zhiwei Sun ◽

Ting Ye ◽

Jingyuan Li ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cell Lines ◽

Human Cancer ◽

Suppressor Activity ◽

Self Renewal ◽

Tumor Suppressor Activity ◽

Lung Cancer Stem Cells ◽

First Time

AbstractIt has been postulated that cancer stem cells (CSCs) are involved in all aspects of human cancer, although the mechanisms governing the regulation of CSC self-renewal in the cancer state remain poorly defined. In the literature, both the pro- and anti-oncogenic activities of autophagy have been demonstrated and are context-dependent. Mounting evidence has shown augmentation of CSC stemness by autophagy, yet mechanistic characterization and understanding are lacking. In the present study, by generating stable human lung CSC cell lines with the wild-type TP53 (A549), as well as cell lines in which TP53 was deleted (H1229), we show, for the first time, that autophagy augments the stemness of lung CSCs by degrading ubiquitinated p53. Furthermore, Zeb1 is required for TP53 regulation of CSC self-renewal. Moreover, TCGA data mining and analysis show that Atg5 and Zeb1 are poor prognostic markers of lung cancer. In summary, this study has elucidated a new CSC-based mechanism underlying the oncogenic activity of autophagy and the tumor suppressor activity of p53 in cancer, i.e., CSCs can exploit the autophagy-p53-Zeb1 axis for self-renewal, oncogenesis, and progression.

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Investigating the Radioresistant Properties of Lung Cancer Stem Cells in the Context of the Tumor Microenvironment

Radiation Research ◽

10.1667/rr14285.1 ◽

2016 ◽

Vol 185 (2) ◽

pp. 169-181 ◽

Cited By ~ 18

Author(s):

Ryan Chan ◽

Pallavi Sethi ◽

Amar Jyoti ◽

Ronald McGarry ◽

Meenakshi Upreti

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Tumor Microenvironment ◽

Cancer Stem Cells ◽

Lung Cancer Stem Cells

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Bone Marrow Mesenchymal Stem Cells (BMSCs) Restrain the Malignant Behaviors of A549 Lung Cancer Cells Under Hypoxia via miR-145

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2022.2926 ◽

2022 ◽

Vol 12 (3) ◽

pp. 597-601

Author(s):

Haibin Song ◽

Heng Zhang ◽

Lei Li

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Cancer Stem Cells ◽

Cell Invasion ◽

A549 Cells ◽

Hypoxia Group ◽

Marrow Mesenchymal Stem Cells ◽

Lung Cancer Stem Cells

Deriving from bone marrow, the bone marrow mesenchymal stem cells (BMSCs) possess multipolar chemotaxis, proliferation potential, along with the capability to differentiate into various types of cells. Moreover, the hypoxic stimulation can effectively induce BMSCs differentiation. This study intends to explore the impediment of BMSCs on malignant behaviors of lung cancer stem cells under hypoxia. A co-culture system of BMSCs with A549 cells was established and then assigned into normoxia group, hypoxia group (50, 100, and 200 nmol/L) followed by analysis of cell viability by CCK-8 assay and miR-145 expression by qRT-PCR. In addition, A549 cells were grouped into NC group, miR-145-mimics group, and miR-145-inhibitors group followed by analysis of cell invasion and levels of miR-145 and Oct4. Hypoxia group exhibited a reduced cell viability and higher miR-145 expression (146.01±21.23%) compared to normoxia group (P < 0.05). Transfection of miR-145-mimic significantly upregulated miR-145 and decreased cell invasion (7.49±1.43%) compared with miR-145-inhibitors group or NC group (P < 0.05). Meanwhile, Oct4 level in miR-145-mimics group (0.934±2.98) was significantly decreased (P < 0.05). In conclusion, under hypoxia condition, the co-culture with BMSCs can upregulated miR-145 level, effectively reduce the viability of lung cancer stem cells and restrain proliferation capability.

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