Hedgehog pathway maintains cell survival under stress conditions, and drives drug resistance in lung adenocarcinoma

Autophagy is a mechanism of lysosomal proteolysis that is utilized to degrade damaged organelles, proteins, and other cellular components. Although key studies demonstrate that autophagy functions as a mechanism of tumor suppression via the degradation of defective pre-malignant cells, autophagy can also be used as a mechanism to break down cellular components under stress conditions to generate the required metabolic materials for cell survival. Autophagy has emerged as an important mediator of resistance to radiation, chemotherapy, and targeted agents. This series of articles highlight the role of autophagy in cancer progression and drug resistance and underscores the need for new and more effective agents that target this process.

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Upregulation of LINC01426 promotes the progression and stemness in lung adenocarcinoma by enhancing the level of SHH protein to activate the hedgehog pathway

Cell Death and Disease ◽

10.1038/s41419-021-03435-y ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Xiaoli Liu ◽

Zuwei Yin ◽

Linping Xu ◽

Huaimin Liu ◽

Lifeng Jiang ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Bioinformatics Analysis ◽

Epithelial Mesenchymal Transition ◽

Mrna Level ◽

Hedgehog Pathway ◽

Biological Processes ◽

Protein Coding ◽

Mesenchymal Transition ◽

Functional Roles ◽

Rip Assay

AbstractLong noncoding RNAs (lncRNAs) play crucial roles in regulating a variety of biological processes in lung adenocarcinoma (LUAD). In our study, we mainly explored the functional roles of a novel lncRNA long intergenic non-protein coding RNA 1426 (LINC01426) in LUAD. We applied bioinformatics analysis to find the expression of LINC01426 was upregulated in LUAD tissue. Functionally, silencing of LINC01426 obviously suppressed the proliferation, migration, epithelial–mesenchymal transition (EMT), and stemness of LUAD cells. Then, we observed that LINC01426 functioned through the hedgehog pathway in LUAD. The effect of LINC01426 knockdown could be fully reversed by adding hedgehog pathway activator SAG. In addition, we proved that LINC01426 could not affect SHH transcription and its mRNA level. Pull-down sliver staining and RIP assay revealed that LINC01426 could interact with USP22. Ubiquitination assays manifested that LINC01426 and USP22 modulated SHH ubiquitination levels. Rescue assays verified that SHH overexpression rescued the cell growth, migration, and stemness suppressed by LINC01426 silencing. In conclusion, LINC01426 promotes LUAD progression by recruiting USP22 to stabilize SHH protein and thus activate the hedgehog pathway.

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A critical role of autocrine sonic hedgehog signaling in human CD138+ myeloma cell survival and drug resistance

Blood ◽

10.1182/blood-2014-03-557298 ◽

2014 ◽

Vol 124 (13) ◽

pp. 2061-2071 ◽

Cited By ~ 48

Author(s):

Zhiqiang Liu ◽

Jingda Xu ◽

Jin He ◽

Yuhuan Zheng ◽

Haiyan Li ◽

...

Keyword(s):

Drug Resistance ◽

Cell Survival ◽

Sonic Hedgehog ◽

Hedgehog Signaling ◽

Critical Role ◽

Myeloma Cell ◽

Sonic Hedgehog Signaling ◽

Key Points

Key Points CD138+ MM cells are a major source of SHH. Autocrine SHH enhances MM drug resistance.

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Leukocyte telomere length is associated with survival and drug resistance in lung adenocarcinoma patients treated with EGFR-TKIs

Annals of Oncology ◽

10.1093/annonc/mdy318.007 ◽

2018 ◽

Vol 29 ◽

pp. vi9

Author(s):

M. Yang ◽

J. Li ◽

N. Zhang

Keyword(s):

Drug Resistance ◽

Lung Adenocarcinoma ◽

Telomere Length ◽

Leukocyte Telomere Length ◽

Egfr Tkis

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Birc6 drives drug resistance and cell survival in chronic myeloid leukemia (1055.6)

The FASEB Journal ◽

10.1096/fasebj.28.1_supplement.1055.6 ◽

2014 ◽

Vol 28 (S1) ◽

Author(s):

Denis Okumu ◽

Merlin Levine ◽

Lauren Jones ◽

Raymond Zhang ◽

Lee Graves

Keyword(s):

Drug Resistance ◽

Chronic Myeloid Leukemia ◽

Cell Survival ◽

Myeloid Leukemia

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P3.02-073 Stromal Hedgehog Pathway Activation Suppresses Growth and Metastasis of Lung Adenocarcinoma

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2017.09.1602 ◽

2017 ◽

Vol 12 (11) ◽

pp. S2263-S2264

Author(s):

S. Kasiri ◽

B. Chen ◽

A. Wilson ◽

U. Barrie ◽

U. Marriam ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Hedgehog Pathway ◽

Pathway Activation

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ERα is an RNA-binding protein sustaining tumor cell survival and drug resistance

Cell ◽

10.1016/j.cell.2021.08.036 ◽

2021 ◽

Author(s):

Yichen Xu ◽

Peiwei Huangyang ◽

Ying Wang ◽

Lingru Xue ◽

Emily Devericks ◽

...

Keyword(s):

Drug Resistance ◽

Tumor Cell ◽

Cell Survival ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Tumor Cell Survival

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PI4KIIIβ is a therapeutic target in chromosome 1q–amplified lung adenocarcinoma

Science Translational Medicine ◽

10.1126/scitranslmed.aax3772 ◽

2020 ◽

Vol 12 (527) ◽

pp. eaax3772 ◽

Cited By ~ 5

Author(s):

Xiaochao Tan ◽

Priyam Banerjee ◽

Edward A. Pham ◽

Florentine U. N. Rutaganira ◽

Kaustabh Basu ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Cell Survival ◽

Cancer Cell ◽

Secretory Vesicle ◽

Effector Proteins ◽

Therapeutic Implications ◽

Chromosome 1Q ◽

Biological Studies ◽

Cancer Cell Survival ◽

Vesicle Biogenesis

Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIβ (PI4KIIIβ). Molecular, biochemical, and cell biological studies show that PI4KIIIβ-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating Golgi phosphoprotein 3 (GOLPH3)–dependent vesicular release from the Golgi. PI4KIIIβ-dependent secreted factors maintain 1q-amplified cancer cell survival and influence prometastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIIIβ antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a dependency on PI4KIIIβ-dependent secretion for cancer cell survival and tumor progression.

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In vitro drug sensitivity of cells from children with leukemia using the MTT assay with improved culture conditions

Blood ◽

10.1182/blood.v76.11.2327.2327 ◽

1990 ◽

Vol 76 (11) ◽

pp. 2327-2336 ◽

Cited By ~ 164

Author(s):

R Pieters ◽

AH Loonen ◽

DR Huismans ◽

GJ Broekema ◽

MW Dirven ◽

...

Keyword(s):

Drug Resistance ◽

Cell Survival ◽

Mtt Assay ◽

Large Scale ◽

Drug Sensitivity ◽

Lymphoblastic Leukemia ◽

Leukemia Cells ◽

Response Curves ◽

Mtt Reduction

Abstract The knowledge about drug resistance in childhood leukemias and acute lymphoblastic leukemia (ALL) in general is limited. This is because of the lack of a suitable in vitro drug sensitivity assay, which is in part due to low in vitro ALL cell survival. We recently adapted the highly efficient 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay to test cells from ALL patients and showed that its results were comparable with those of the DiSC assay, up to now the most valid but laborious assay. In this study, in vitro drug sensitivity was assessed in cells from 82 children with leukemia, 79 of whom had ALL, with the MTT assay. Dose response curves were obtained for 6-mercaptopurine, 6-thioguanine (6-TG), prednisolone (Pred), daunorubicin (DNR), vincristine (VCR), cytosine arabinoside (Ara-C), L- asparaginase (L-Asp), mafosfamide, and mustine. A cytotoxic effect of methotrexate could be detected in only a few cases. Large interindividual differences in drug sensitivity were detected. Compared with leukemia cells from newly diagnosed patients, leukemia cells from relapsed patients were significantly more in vitro resistant to 6-TG, Pred, Ara-C, mafosfamide and mustine but not to DNR, VCR, and L-Asp. Improvements of culture medium and methods to increase MTT reduction were studied. From 10 components tested, addition of insulin and bovine serum albumin to serum-containing medium improved ALL cell survival. Addition of succinate did not increase the amount of MTT reduction. We conclude that the in vitro MTT assay highly facilitates large-scale studies on drug resistance of ALL patients that can lead to rational improvements in existing treatment protocols.

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The Preparation, Determination of a Flexible Complex Liposome Co-Loaded with Cabazitaxel and β-Elemene, and Animal Pharmacodynamics on Paclitaxel-Resistant Lung Adenocarcinoma

Molecules ◽

10.3390/molecules24091697 ◽

2019 ◽

Vol 24 (9) ◽

pp. 1697 ◽

Cited By ~ 5

Author(s):

Yi-Ying Zeng ◽

Yi-Jun Zeng ◽

Na-Na Zhang ◽

Chen-Xi Li ◽

Tian Xie ◽

...

Keyword(s):

Drug Resistance ◽

Lung Adenocarcinoma ◽

Malignant Tumors ◽

Clinical Applications ◽

Paclitaxel Resistance ◽

Release Rates ◽

Dialysis Method ◽

Difficult Challenge ◽

Weibull Equation

Paclitaxel is highly effective at killing many malignant tumors; however, the development of drug resistance is common in clinical applications. The issue of overcoming paclitaxel resistance is a difficult challenge at present. In this study, we developed nano drugs to treat paclitaxel-resistant lung adenocarcinoma. We selected cabazitaxel and β-elemene, which have fewer issues with drug resistance, and successfully prepared cabazitaxel liposome, β-elemene liposome and cabazitaxel-β-elemene complex liposome with good flexibility. The encapsulation efficiencies of cabazitaxel and β-elemene in these liposomes were detected by precipitation microfiltration and microfiltration centrifugation methods, respectively. Their encapsulation efficiencies were all above 95%. The release rates were detected by a dialysis method. The release profiles of cabazitaxel and β-elemene in these liposomes conformed to the Weibull equation. The release of cabazitaxel and β-elemene in the complex liposome were almost synchronous. The pharmacodynamics study showed that cabazitaxel flexible liposome and β-elemene flexible liposome were relatively good at overcoming paclitaxel resistance on paclitaxel-resistant lung adenocarcinoma. As the flexible complex liposome, the dosage of cabazitaxel could be reduced to 25% that of the cabazitaxel injection while retaining a similar therapeutic effect. It showed that β-elemene can replace some of the cabazitaxel, allowing the dosage of cabazitaxel to be reduced, thereby reducing the drug toxicity.

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