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Hedgehog Signaling Pathway and Autophagy in Cancer.

ABSTRACT: Hedgehog (Hh) pathway controls complex developmental processes in vertebrates. Abnormal activation of Hh pathway is responsible for tumorigenesis and maintenance of multiple cancers, and thus addressing this represents promising therapeutic opportunities. In recent years, two Hh inhibitors have been approved for basal cell carcinoma (BCC) treatment and show extraordinary clinical outcomes. Meanwhile, a series of novel agents are being developed for the treatment of several cancers, including lung cancer, leukemia, and pancreatic cancer. Unfortunately, Hh inhibition fails to show satisfactory benefits in these cancer types compared with the success stories in BCC, highlighting the need for better understanding of Hh signaling in cancer. Autophagy, a conserved biological process for cellular component elimination, plays critical roles in the initiation, progression, and drug resistance of cancer, and therefore, implied potential to be targeted. Recent evidence demonstrated that Hh signaling interplays with autophagy in multiple cancers. Importantly, modulating this crosstalk exhibited noteworthy capability to sensitize primary and drug-resistant cancer cells to Hh inhibitors, representing an emerging opportunity to reboot the efficacy of Hh inhibition in those insensitive tumors, and to tackle drug resistance challenges. This review will highlight recent advances of Hh pathway and autophagy in cancers, and focus on their crosstalk and the implied therapeutic opportunities.

SUBMITTER: Zeng X

PROVIDER: S-EPMC6121518 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Hedgehog Signaling Pathway and Autophagy in Cancer.

Zeng Xian X Ju Dianwen D

International journal of molecular sciences 20180803 8

Hedgehog (Hh) pathway controls complex developmental processes in vertebrates. Abnormal activation of Hh pathway is responsible for tumorigenesis and maintenance of multiple cancers, and thus addressing this represents promising therapeutic opportunities. In recent years, two Hh inhibitors have been approved for basal cell carcinoma (BCC) treatment and show extraordinary clinical outcomes. Meanwhile, a series of novel agents are being developed for the treatment of several cancers, including lun ...[more]

PMID: 30081498

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Project description:Hedgehog (Hh) signaling plays an important role in embryonic development and in the regulation of a variety of cellular functions. Aberrant activation of Hh signaling has been implicated in several human cancers including hepatocellular carcinoma (HCC). In this study we examined the pathobiological functions and molecular mechanisms of the Hh signaling pathway in HCC cells. Treatment of cultured human HCC cells (Huh7, Hep3B, and HepG2) with the Hh signaling ligand (recombinant Shh) or agonist, SAG and purmorphamine, prevented the induction of autophagy. In contrast, GANT61 (a small molecule inhibitor of Gli1 and Gli2) induced autophagy, as determined by immunoblotting for microtubule-associated protein light chain 3 (LC3) and p62, GFP-LC3 puncta, monodansylcadaverine (MDC) staining, and transmission electron microscopy. Hh inhibition-induced autophagy was associated with up-regulation of Bnip3, as determined by immunoblotting and real-time polymerase chain reaction (PCR) assay. Knockdown of Bnip3 by RNAi impaired GANT61-induced autophagy. Additionally, Hh inhibition-induced autophagy was associated with Bnip3-mediated displacement of Bcl-2 from Beclin-1, as determined by immunoblotting and immunoprecipitation assays. Furthermore, inhibition of Hh signaling increased HCC cell apoptosis and decreased cell viability, as determined by caspase and WST-1 assays. Pharmacological or genetic inhibition of autophagy by 3-methyladenine (3-MA) or Beclin-1 small interfering RNA (siRNA) partially suppressed GANT61-induced cell apoptosis and cytotoxicity. In a tumor xenograft model using SCID mice inoculated with Huh7 cells, administration of GANT61 inhibited tumor formation and decreased tumor volume; this effect was partially blocked by the autophagy inhibitor, 3-MA.These findings provide novel evidence that Hh inhibition induces autophagy through up-regulation of Bnip3 and that this mechanism contributes to apoptosis. Therefore, the status of autophagy is a key factor that determines the therapeutic response to Hh-targeted therapies.

Dataset Information

Hedgehog Signaling Pathway and Autophagy in Cancer.

Publications

Hedgehog Signaling Pathway and Autophagy in Cancer.

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