Hedgehog Inhibition Upregulates TRK Expression to Antagonize Tumor Suppression in Small Cell Lung Cancer Cells

Onishi, Hideya; Nakamura, Katsuya; Nagai, Sonoko; Yanai, Kosuke; Yamasaki, Akio; Kawamoto, Makoto; Imaizumi, Akira; Morisaki, T.

doi:10.21873/anticanres.11910

Cited by 3 publications

(2 citation statements)

References 21 publications

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“…It is important to understand the differences in AsPC-1 cells compared to the other two cell lines. For example, in the small cell lung cancer (SCLC) line, comprising SBC-5 cells, Hedgehog (Hh) signaling is inversely correlated with TrkB/BDNF signaling, and inhibition of Hh signaling leads to the activation of TrkB/BDNF signaling to induce malignant phenotypes (9). Some factors or signaling pathways may contribute to this discrepancy.…”

Section: Discussionmentioning

confidence: 99%

TrkB/BDNF Signaling Could Be a New Therapeutic Target for Pancreatic Cancer

et al. 2021

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Background/Aim: Tropomyosin-related kinase B (TrkB)/brain-derived neurotrophic factor (BDNF) signaling plays a role in inducing malignant phenotypes in several aggressive types of cancers. To create a conclusive therapy targeting TrkB/BDNF signaling in solid refractory cancers, the biological significance of TrkB/BDNF signaling was analyzed in pancreatic ductal adenocarcinoma (PDAC) cells. Materials and Methods: Three PDAC cell lines were used as target cells to investigate proliferation and invasiveness. Small interfering RNA (siRNA) and the TrkB tyrosine kinase inhibitor k252a were used as TrkB/BDNF signaling inhibitors. Results: All PDAC cell lines expressed TrkB and BDNF. When TrkB and BDNF were inhibited by siRNA or k252a, the invasiveness of PANC-1 and SUIT-2 cells significantly decreased. When TrkB was inhibited by siRNA or k252a, proliferation was significantly inhibited in PDAC cells. Conclusion: TrkB/BDNF signaling may be a new therapeutic target for PDAC. Therapies targeting TrkB/BDNF signaling may be a conclusive cancer therapy for refractory solid cancer.

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Section: Discussionmentioning

confidence: 99%

TrkB/BDNF Signaling Could Be a New Therapeutic Target for Pancreatic Cancer

et al. 2021

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“…Matrigel invasion assay and migration assay. The invasiveness of SBC-5 cells was assessed based on the invasion of cells through Matrigel-coated transwell inserts as described previously (8). In brief, the upper surface of a filter (pore size, 8.0 μm; BD Biosciences, Heidelberg, Germany) was coated with basement membrane Matrigel (BD Biosciences).…”

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confidence: 99%

Liprin-α4 as a New Therapeutic Target for SCLC as an Upstream Mediator of HIF1α

et al. 2019

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Background/Aim: Small-cell lung cancer (SCLC) remains one of deadliest types of cancers. Cisdiamminedichloroplatinum (CDDP) is a key chemotherapeutic agent for SCLC, however, its therapeutic effect is limited. Recently, hypoxia in the cancer microenvironment has been suggested to influence the effect of cancer therapy. Materials and Methods: Using small interfering RNA inhibition of leukocyte common antigen-related interacting protein alpha 4 (liprin-α4), and of hypoxia-inducible factor (HIF)-1α, proliferation, invasion, migration and chemosensitivity were investigated in SBC-5 SCLC cells, under normoxia and hypoxia. Results: Liprin-α4 was found to contribute to proliferation, but not migration and invasion of SBC-5 cells both under normoxia and hypoxia. Inhibition of liprin-α4 increased chemosensitivity of SBC-5 cells under hypoxia. Liprin-α4 signaling occurs through mitogen-activated protein kinase pathways via activation of HIF1α expression. Inhibition of HIF1α reduced proliferation and increased chemosensitivity of SBC-5 cells under hypoxia. Conclusion: Liprin-α4 inhibition may enhance the effect of CDDP and liprin-α4 might be a novel therapeutic target in SCLC.Small-cell lung cancer (SCLC) is still a refractory cancer for which there are few therapeutic strategies. Cisdiamminedichloroplatinum (CDDP) is a key chemotherapeutic agent, however, its effect is limited. Developing a new effective therapeutic strategy against SCLC and increasing the effect of existing agents is earnestly required.The microenvironment surrounding cancer tissue is important in considering cancer therapy. This microenvironment includes tumor-infiltrating immune cells, fibrosis, and desmoplasia, as well as cytokines and other molecules. Hypoxia is also thought to occur in the cancer microenvironment. The tumor local site is extremely hypoxic, with an oxygen concentration of approximately 1% O 2 (1). Biological functioning is altered under hypoxia. Therefore, the cell phenotype should especially be considered when investigating proliferation, invasion, and chemosensitivity under hypoxia rather than under normoxia which is a usual experimental condition.Liprins are major protein constituents of synapses and play a pivotal role in the organization of synaptic vesicles and neurotransmitter receptors (2). Liprin-α belongs to the LAR family of receptor protein tyrosine phosphatase (3, 4). Among liprin members, liprin-1α is well researched and recently its interaction with some cancer types has been reported (5, 6). On the other hand, the role of liprin-α4 remains unclear with regard to cancer biology. Previously we showed that liprin-α4 has potential as a new therapeutic target for refractory pancreatic cancer (7). In the present study, we evaluated whether liprin-α4 might be a therapeutic target in SCLC, which like pancreatic cancer is a refractory type of neuroendocrine cancer. Materials and MethodsCell culture and reagents. A human SCLC cell line (SBC-5: American Type Culture Collection, Manassas, VA, USA) was maintained in RPMI-1640 me...

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Addressing cancer signal transduction pathways with antisense and siRNA oligonucleotides

Juliano¹

2020

NAR Cancer

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Signal transduction pathways play key roles in the initiation, progression and dissemination of cancer. Thus, signaling molecules are attractive targets for cancer therapeutics and enormous efforts have gone into the development of small molecule inhibitors of these pathways. However, regrettably, there has been only moderate progress to date, primarily in connection with the RAS signaling pathway. Oligonucleotide-based drugs potentially offer several advantages for addressing signaling pathways, including their exquisite selectivity and their ability to exploit both enzymatic and nonenzymatic targets. Nonetheless, there are problems inherent in the oligonucleotide approach, not the least being the challenge of effectively delivering these complex molecules to intracellular sites within tumors. This survey article will provide a selective review of recent studies where oligonucleotides were used to address cancer signaling and will discuss both positive aspects and limitations of those studies. This will be set in the context of an overview of various cancer signaling pathways and small molecule approaches to regulate those pathways. The survey will also evaluate the challenges and opportunities implicit in the oligonucleotide-based approach to cancer signaling and will point out several possibilities for future research.

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Hedgehog Inhibition Upregulates TRK Expression to Antagonize Tumor Suppression in Small Cell Lung Cancer Cells

Abstract: These results suggest that Hh inhibition increases TrkB expression to counter tumor suppression in SBC-5 cells. The combined use of TRKB and Hh inhibitors may, therefore, be useful for the treatment of refractory SCLC.

Cited by 3 publications

References 21 publications

TrkB/BDNF Signaling Could Be a New Therapeutic Target for Pancreatic Cancer

TrkB/BDNF Signaling Could Be a New Therapeutic Target for Pancreatic Cancer

Liprin-α4 as a New Therapeutic Target for SCLC as an Upstream Mediator of HIF1α

Addressing cancer signal transduction pathways with antisense and siRNA oligonucleotides

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