Molecular pathways: the role of primary cilia in cancer progression and therapeutics with a focus on Hedgehog signaling - PubMed (original) (raw)

Molecular pathways: the role of primary cilia in cancer progression and therapeutics with a focus on Hedgehog signaling

Nadia B Hassounah et al. Clin Cancer Res. 2012.

Abstract

Abnormal Hedgehog (Hh) pathway activity has been reported in many cancers, including basal cell carcinomas, medulloblastomas, rhabdomyosarcomas, glioblastomas, and breast and prostate cancers. For this reason, the Hh pathway is a flourishing area for development of anticancer drugs such as Hh ligand antagonists (e.g., 5E1 and robotnikinin), Smo inhibitors (e.g., GDC-0449 and IPI-926), and Gli transcriptional activity inhibitors (e.g., GANT58 and GANT61). It is now clear that primary cilia are required for activation of the Hh pathway in normal vertebrate cells. It is in the primary cilium that both positive and negative effectors of the Hh pathway are processed by posttranslational modifications. In many cancers, preliminary results suggest that primary cilia are lost. As drugs that inhibit different steps of the Hh pathway are developed, it will be important to consider how these drugs will function in the context of primary cilia in the tumor environment. Here, we discuss why some of the Hh inhibitors may be ineffective if primary cilia are lost on cancer cells. Understanding the relationships between clinical inhibitors of the Hh pathway and the presence or absence of primary cilia may turn out to be critical for targeting these therapeutics to the correct population of patients and improving their efficacy. Further work is needed in this area to maximize the potential of these exciting therapeutic targets.

©2012 AACR.

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Conflict of interest statement

DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

No potential conflicts of interest were disclosed.

Figures

Figure 1

Figure 1. Regulation of the Hedgehog Pathway by Primary Cilia in Normal Cells

Structure of Primary Cilium: The primary cilium contains microtubule bundles (9 doublets arrayed as a cylindrical structure) that are nucleated from the basal body. The microtubule bundles are enclosed in a ciliary membrane that is continuous, but distinct, from the plasma membrane. At the base of the cilium are transition fibers localized in the transition zone. This transition zone is known to restrict passive diffusion of proteins in and out of the cilium. Kinesin 2 moves the IFT complex and its ‘cargo’ (e.g. Gli, Ptch and Smo) towards the plus-end of microtubules (ciliary tip). Dynein 2 moves the IFT complex and its ‘cargo’ towards the minus-end of microtubules (cell body). Hh Regulation: In the absence of Hh (left side) Gli protein is converted to its repressor form (GliR). Also in the absence of Hh, Ptch1 is localized to the ciliary membrane and Smo is kept out of the cilium. In the presence of Hh (right side) Gli protein levels increase in the cilium and Gli is processed into the activator form (GliA) for transport out of the cilium and into the nucleus where it activates Hh target genes. In the presence of Hh, Ptch1 moves out of the cilium and Smo moves into the cilium where it promotes formation of the activator form of Gli (GliA).

Figure 2

Figure 2. The Role of Cilia in Hedgehog Pathway Activation in Cancer Cells

A. Cancer-Associated overexpression of Hh ligands or mutations in genes such as Ptch1 or Smo, which lie upstream of cilia, will only result in activation of the Hh pathway by increasing GliA levels if cilia are present. If cilia are present, then inhibitors targeting Hh ligand, Smo, and Gli trafficking (grey boxes) will be effective. Inhibitors that target Gli activity downstream of cilia (white box) will also be effective in reducing the Hh pathway in this context. B. Cancer-associated overexpression of Gli1 (GliA) in the presence of cilia will result in low levels of Hh pathway activation. In this context, cilia make the repressor form of Gli (GliR) counterbalancing GliA to reduce over activation of the Hh pathway. Mutations in REN(KCTD11) can also result in increased GliA activity. As this activation is downstream of cilia only the downstream Gli targeting inhibitors (white box) are predicted to be effective. C. Cancer-associated overexpression of Hh ligands or mutations in genes such as Ptch or Smo, which lie upstream of cilia, will not activate the Hh pathway in the absence of cilia. D. Cancer-associated mutations downstream of cilia such as overexpression of Gli1 (GliA) or mutations in Ren(KCTD11) have been documented in cancers and will turn on the Hh pathway in the absence of cilia due to high GliA and low GliR. Therefore, only downstream Gli targeting inhibitors (white box) are predicted to be effective in this scenario.

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