CDO, an Hh-Coreceptor, Mediates Lung Cancer Cell Proliferation and Tumorigenicity through Hedgehog Signaling

Leem, Young-Eun; Ha, Hye-Lim; Bae, Ju-Hyeon; Baek, Kwan-Hyuck; Kang, Jong‐Sun

doi:10.1371/journal.pone.0111701

Cited by 11 publications

(6 citation statements)

References 52 publications

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“…Notably, CycT diminished the rates of oxygen consumption in cancer cells largely to the same extent as glutamine depletion. Likewise, another SMO inhibitor SANT1 [ 21 , 22 ] diminished oxygen consumption in NSCLC cells, as expected. These results indicate that CycT can cause the same effect as glutamine depletion on cancer cell metabolism and aerobic respiration.…”

Section: Resultssupporting

confidence: 76%

Cyclopamine tartrate, an inhibitor of Hedgehog signaling, strongly interferes with mitochondrial function and suppresses aerobic respiration in lung cancer cells

et al. 2016

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BackgroundAberrant Hedgehog (Hh) signaling is associated with the development of many cancers including prostate cancer, gastrointestinal cancer, lung cancer, pancreatic cancer, ovarian cancer, and basal cell carcinoma. The Hh signaling pathway has been one of the most intensely investigated targets for cancer therapy, and a number of compounds inhibiting Hh signaling are being tested clinically for treating many cancers. Lung cancer causes more deaths than the next three most common cancers (colon, breast, and prostate) combined. Cyclopamine was the first compound found to inhibit Hh signaling and has been invaluable for understanding the function of Hh signaling in development and cancer. To find novel strategies for combating lung cancer, we decided to characterize the effect of cyclopamine tartrate (CycT), an improved analogue of cyclopamine, on lung cancer cells and its mechanism of action.MethodsThe effect of CycT on oxygen consumption and proliferation of non-small-cell lung cancer (NSCLC) cell lines was quantified by using an Oxygraph system and live cell counting, respectively. Apoptosis was detected by using Annexin V and Propidium Iodide staining. CycT’s impact on ROS generation, mitochondrial membrane potential, and mitochondrial morphology in NSCLC cells was monitored by using fluorometry and fluorescent microscopy. Western blotting and fluorescent microscopy were used to detect the levels and localization of Hh signaling targets, mitochondrial fission protein Drp1, and heme-related proteins in various NSCLC cells.ResultsOur findings identified a novel function of CycT, as well as another Hh inhibitor SANT1, to disrupt mitochondrial function and aerobic respiration. Our results showed that CycT, like glutamine depletion, caused a substantial decrease in oxygen consumption in a number of NSCLC cell lines, suppressed NSCLC cell proliferation, and induced apoptosis. Further, we found that CycT increased ROS generation, mitochondrial membrane hyperpolarization, and mitochondrial fragmentation, thereby disrupting mitochondrial function in NSCLC cells.ConclusionsTogether, our work demonstrates that CycT, and likely other Hh signaling inhibitors, can interrupt NSCLC cell function by promoting mitochondrial fission and fragmentation, mitochondrial membrane hyperpolarization, and ROS generation, thereby diminishing mitochondrial respiration, suppressing cell proliferation, and causing apoptosis. Our work provides novel mechanistic insights into the action of Hh inhibitors in cancer cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2200-x) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 76%

Cyclopamine tartrate, an inhibitor of Hedgehog signaling, strongly interferes with mitochondrial function and suppresses aerobic respiration in lung cancer cells

et al. 2016

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“…The involved pathways are mostly oncogenic, such as PI3K-AKT, RAS-MEK, and TGF-β [ 11 ]. It was initially believed that NSCLC substantially exhibited the activation of the canonical Hh pathway [ 13 , 14 , 16 , 19 , 26 , 27 , 29 , 32 , 34 , 35 , 39 , 50 ]. Nevertheless, emerging evidence also indicates that the non-canonical Hh pathway outperforms the canonical one in NSCLC [ 17 , 22 , 23 , 36 , 38 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

“…Basbaum’s lab demonstrated that cigarette-smoke induced the Hh pathway in human primary or immortalized bronchial epithelial cells and thus elicited tumorigenesis in these cells [ 19 ]. Several lines of evidence suggest that the Hh pathway plays an important role in NSCLC tumorigenesis via regulating stemness features [ 20 , 21 , 22 , 23 , 24 ], drug resistance [ 25 , 26 , 27 , 28 ], epithelial-mesenchymal transition, invasion, migration [ 16 , 29 , 30 , 31 , 32 , 33 , 34 ], and cellular proliferation [ 17 , 31 , 32 , 33 , 35 , 36 , 37 , 38 , 39 ]. Taking a close relationship between the Hh pathway and LSCC into consideration, we considered whether Hh signaling served as an upstream pathway to modulate the expression of the PRR11-SKA2 gene pair.…”

Section: Introductionmentioning

confidence: 99%

HEDGEHOG/GLI Modulates the PRR11-SKA2 Bidirectional Transcription Unit in Lung Squamous Cell Carcinomas

Sun

Zhang

et al. 2021

Genes

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We previously demonstrated that proline-rich protein 11 (PRR11) and spindle and kinetochore associated 2 (SKA2) constituted a head-to-head gene pair driven by a prototypical bidirectional promoter. This gene pair synergistically promoted the development of non-small cell lung cancer. However, the signaling pathways leading to the ectopic expression of this gene pair remains obscure. In the present study, we first analyzed the lung squamous cell carcinoma (LSCC) relevant RNA sequencing data from The Cancer Genome Atlas (TCGA) database using the correlation analysis of gene expression and gene set enrichment analysis (GSEA), which revealed that the PRR11-SKA2 correlated gene list highly resembled the Hedgehog (Hh) pathway activation-related gene set. Subsequently, GLI1/2 inhibitor GANT-61 or GLI1/2-siRNA inhibited the Hh pathway of LSCC cells, concomitantly decreasing the expression levels of PRR11 and SKA2. Furthermore, the mRNA expression profile of LSCC cells treated with GANT-61 was detected using RNA sequencing, displaying 397 differentially expressed genes (203 upregulated genes and 194 downregulated genes). Out of them, one gene set, including BIRC5, NCAPG, CCNB2, and BUB1, was involved in cell division and interacted with both PRR11 and SKA2. These genes were verified as the downregulated genes via RT-PCR and their high expression significantly correlated with the shorter overall survival of LSCC patients. Taken together, our results indicate that GLI1/2 mediates the expression of the PRR11-SKA2-centric gene set that serves as an unfavorable prognostic indicator for LSCC patients, potentializing new combinatorial diagnostic and therapeutic strategies in LSCC.

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“…The functions of the SHH signaling pathway have been previously explored in various types of human tumors, including B-cell lymphoma [ 22 ], malignant pleural mesothelioma [ 23 ], medulloblastoma [ 24 , 25 ], pancreatic cancer [ 26 , 27 ], prostate cancer [ 28 , 29 ], lung cancer [ 30 , 31 ], basal cell carcinoma [ 13 ], and chronic myelogeneous leukemia [ 32 ]. However, this is the first study to explore the role of autocrine SHH signaling in GC.…”

Section: Discussionmentioning

confidence: 99%

Autocrine Sonic hedgehog signaling promotes gastric cancer proliferation through induction of phospholipase Cγ1 and the ERK1/2 pathway

Zhai

Chen

et al. 2016

J Exp Clin Cancer Res

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BackgroundSonic hedgehog (SHH) plays critical roles in cell growth and development. Tumor cells express SHH, which can promote cell proliferation and epithelial-to-mesenchymal transition. However, the autocrine SHH pathway has not been described in gastric cancer. The aim of this study was to explore molecular mechanisms underlying autocrine SHH signaling in gastric cancer cells.MethodsSHH expression was assessed using immunohistochemistry and the results were compared with clinicopathologic parameters, including survival. Using gastric cancer cell lines, we measured SHH mRNA and protein expression, and studied the effects of SHH signaling on cell proliferation and SHH secretion. We also studied the effects of an inhibitor of PLC-γ1 on phosphorylation of phospholipase Cγ1 and extracellular signal-regulated kinases (ERK)1/2.ResultsSHH protein expression in gastric cancer tissue was significantly higher compared with that in normal gastric tissue (P < 0.001), and the increased expression was significantly associated with pT staging (P = 0.004), pN staging (P = 0.018), pM staging (P = 0.006), and pTNM staging (P < 0.001). In multivariate analyses, overall survival in gastric cancer was significantly shorter in cases with high SHH expression (HR = 1.734, 95 % CI: 1.109–2.713, P = 0.016). The AGS and SGC-7901 gastric cancer cell lines expressed SHH mRNA and protein. In these cell lines, SHH promoted carcinogenesis through activation of the PLCγ1-ERK1/2 pathway, resulting in increased cell proliferation and survival.ConclusionsIncreased SHH expression is associated with shorter survival in gastric cancer patients, and SHH could represent a useful biomarker or therapeutic target for this disease.

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CDO, an Hh-Coreceptor, Mediates Lung Cancer Cell Proliferation and Tumorigenicity through Hedgehog Signaling

Cited by 11 publications

References 52 publications

Cyclopamine tartrate, an inhibitor of Hedgehog signaling, strongly interferes with mitochondrial function and suppresses aerobic respiration in lung cancer cells

Cyclopamine tartrate, an inhibitor of Hedgehog signaling, strongly interferes with mitochondrial function and suppresses aerobic respiration in lung cancer cells

HEDGEHOG/GLI Modulates the PRR11-SKA2 Bidirectional Transcription Unit in Lung Squamous Cell Carcinomas

Autocrine Sonic hedgehog signaling promotes gastric cancer proliferation through induction of phospholipase Cγ1 and the ERK1/2 pathway

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