Hedgehog pathway maintains cell survival under stress conditions, and drives drug resistance in lung adenocarcinoma

Abstract

Hedgehog (HH) pathway plays an important role in embryonic development, but is largely inactive in adult except for tissue repair. Aberrant activation of HH pathway has been found in a variety of cancer types. In non-small cell lung cancer, however, the role and importance of HH pathway remain controversial. In the current study, we found that HH pathway was maintained in low activity in lung adenocarcinoma (LAC) cells under normal culture condition, but was highly induced in response to stress conditions. Activation of HH pathway promoted cell survival, growth, and invasion partially through HGF and MET signaling. Hedgehog-Interacting Protein (HHIP), a cell-surface negative regulator of HH pathway, was epigenetically silenced in LAC. Overexpression of HHIP blocked the activation of HH and HGF/MET pathways, and made cells significantly more susceptible to stress conditions. In LAC cells with acquired resistance to Epidermal Growth Factor Receptor Tyrosin Kinase Inhibitor (EGFR-TKI), we found that a part of tumor cells were much more sensitive to HH or HGF/MET inhibitors, suggesting an oncogenic addiction shift from EGFR to HH and HGF/MET pathways. In conclusion, this study showed that HH pathway is a survival signaling that drives LAC cell growth under stress conditions, and HHIP is a key regulator to block the induction of HH pathway. Targeting the HH pathway through inhibitors or HHIP thus holds promise to address EGFR-TKI resistance in LAC in clinic.

Efficacy of continuous EGFR-inhibition and role of Hedgehog in EGFR acquired resistance in human lung cancer cells with activating mutation of EGFR

“…Infact, protein lysates from harvested resistant tumors showed higher vimentin levels and EGFR-inhibitors resistant cancer cells established in vitro showed high invasive and migrative abilities. Consistently with our previous findings, Hh signaling was confirmed as an important mediator of resistance to EGFR-TKIs inhibitors for first-generation EGFR-TKIs [6, 30–32]. Further, in the present study, we demonstrated that Hh activation is involved also in resistance to second and third generation EGFR-TKIs.…”

Capsaicin triggers autophagic cell survival which drives epithelial mesenchymal transition and chemoresistance in bladder cancer cells in an Hedgehog-dependent manner

“…The Hedgehog pathway has been found to regulate autophagy and EMT [24–26]. Thus, we first evaluated by quantitative real time PCR (qRT-PCR) the expression of different members of Hedgehog signaling pathway, Shh, Ihh and Dhh ligands, their specific receptors, Patched 1 and 2 (Ptch1 and Ptch2) and some related genes such as Zeb1, Zeb2, ALCAM and VEGFA in BC cells treated with CPS for 120 h. Upregulation of the Dhh/Ptch2/Zeb2 pathway as well as downregulation of Shh or Ihh/Ptch1/Zeb1 genes were observed in CPS-treated BC cells as respect to untreated cells.…”

“…Hedgehog signaling pathway activation is positively correlated with chemoresitance in cancer cells [24, 27]. Thus, we finally investigated the drug-sensitivity of CPS-induced EMT cells to chemotherapeutic agents commonly used in BC therapy.…”

Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas

“…Finally, Hh signaling can regulate cancer stem cell numbers as well as the tumor microenvironment, creating conditions that promote tumor growth. This role of Hh signaling can be found in leukemia and liver cancer, and is often responsible for the recurrence of cancer through resistance to chemotherapy and radiotherapy 24–33. Dys-regulation of any component of the Hh pathway leading to its aberrant activation can result in malignant conditions through these mechanisms.…”