Mitogen-activated protein kinases and Hedgehog-GLI signaling in cancer: A crosstalk providing therapeutic opportunities?

Semin Cancer Biol. 2015 Dec;35:154-67. doi: 10.1016/j.semcancer.2015.08.003. Epub 2015 Aug 17.

Abstract

The Hedgehog-GLI (HH-GLI) signaling is of critical importance during embryonic development, where it regulates a number of cellular processes, including patterning, proliferation and differentiation. Its aberrant activation has been linked to several types of cancer. HH-GLI signaling is triggered by binding of ligands to the transmembrane receptor patched and is subsequently mediated by transcriptional effectors belonging to the GLI family, whose function is fine tuned by a series of molecular interactions and modifications. Several HH-GLI inhibitors have been developed and are in clinical trials. Similarly, the mitogen-activated protein kinases (MAPK) are involved in a number of biological processes and play an important role in many diseases including cancer. Inhibiting molecules targeting MAPK signaling, especially those elicited by the MEK1/2-ERK1/2 pathway, have been developed and are moving into clinical trials. ERK1/2 may be activated as a consequence of aberrant activation of upstream signaling molecules or during development of drug resistance following treatment with kinase inhibitors such as those for PI3K or BRAF. Evidence of a crosstalk between HH-GLI and other oncogenic signaling pathways has been reported in many tumor types, as shown by recent reviews. Here we will focus on the interaction between HH-GLI and the final MAPK effectors ERK1/2, p38 and JNK in cancer in view of its possible implications for cancer therapy. Several reports highlight the existence of a consistent crosstalk between HH signaling and MAPK, especially with the MEK1/2-ERK1/2 pathway, and this fact should be taken into consideration for designing optimal treatment and prevent tumor relapse.

Keywords: Cancer; Combination therapy; ERK; GLI; Hedgehog; MAPK; Signal transduction; Signaling integration; Targeted therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Hedgehog Proteins / antagonists & inhibitors
  • Hedgehog Proteins / metabolism*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Signaling System
  • Mitogen-Activated Protein Kinase 7 / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neoplasms / diagnosis
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Oncogene Proteins / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Signal Transduction* / drug effects
  • Trans-Activators / metabolism*
  • Zinc Finger Protein GLI1
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Hedgehog Proteins
  • Oncogene Proteins
  • Protein Kinase Inhibitors
  • Trans-Activators
  • Zinc Finger Protein GLI1
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 7
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases