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Blocking SHH/Patched interaction triggers tumor growth inhibition through Patched-induced apoptosis.
Cancer Res. 2020 Feb 14 [Online ahead of print]CR

Abstract

The Sonic Hedgehog (SHH) pathway plays a key role in cancer. Alterations of SHH canonical signaling, causally linked to tumor progression, have become rational targets for cancer therapy. However, Smoothened (Smo) inhibitors have failed to show clinical benefit in patients with cancers displaying SHH autocrine/paracrine expression. We reported earlier that the SHH receptor Patched (Ptc) is a dependence receptor that triggers apoptosis in the absence of SHH through a pathway that differs from the canonical one, thus generating a state of dependence on SHH for survival. Here, we propose a dual function for SHH: its binding to Ptc not only activates the SHH canonical pathway but also blocks Ptc-induced apoptosis. 80%, 64% and 8% of human colon, pancreatic and lung cancer cells, respectively, overexpressed SHH at transcriptional and protein levels. In addition, SHH-overexpressing cells expressed all the effectors of the Ptc-induced apoptotic pathway. While the canonical pathway remained unchanged, autocrine SHH interference in colon, pancreatic and lung cell lines triggered cell death through Ptc pro-apoptotic signaling. In vivo, SHH interference in colon cancer cell lines decreased primary tumor growth and metastasis. Therefore, the anti-tumor effect associated to SHH deprivation, usually thought to be a consequence of the inactivation of the canonical SHH pathway, is due to the engagement of Ptc pro-apoptotic activity. Together, these data strongly suggest that therapeutic strategies based on the disruption of SHH/Ptc interaction in SHH-overexpressing cancers should be explored.

Authors+Show Affiliations

Univerisity Health Network, Princess Margaret Cancer Centre.Apoptosis, Cancer and Development, University of Lyon-CRCL.Apoptosis, Cancer and Development, University of Lyon-CRCL.Centre de Recherche en Cancérologie de Lyon, INSERM 1052, CNRS 5286.UMR-S1052, Centre de Recherche en Cancérologie.Apoptosis, Cancer and Development, University of Lyon-CRCL.Plateforme Anatomopathologie-Recherche, Département de Recherche Translationnelle et Innovation, Centre Léon Bérard.Centre Léon Bérard, Cheney A, UMR INSERM U1052/CNRS 5286.Department of chemistry, University of Rochester.Department of Chemistry,, University of Rochester.Apoptosis, Cancer and Development, University of Lyon-CRCL.Tumoral escape, CRCL.LabEX DEVweCAN, Centre de Recherche en Cancérologie de Lyon.Apoptosis, Cancer and Development, University of Lyon-CRCL patrick.mehlen@lyon.unicancer.fr.Apoptosis, Cancer and Development, University of Lyon-CRCL.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32060146

Citation

Bissey, Pierre-Antoine, et al. "Blocking SHH/Patched Interaction Triggers Tumor Growth Inhibition Through Patched-induced Apoptosis." Cancer Research, 2020.
Bissey PA, Mathot P, Guix C, et al. Blocking SHH/Patched interaction triggers tumor growth inhibition through Patched-induced apoptosis. Cancer Res. 2020.
Bissey, P. A., Mathot, P., Guix, C., Jasmin, M., Goddard, I., Costechareyre, C., Gadot, N., Delcros, J. G., Mali, S. M., Fasan, R., Arrigo, A. P., Dante, R., Ichim, G., Mehlen, P., & Fombonne, J. (2020). Blocking SHH/Patched interaction triggers tumor growth inhibition through Patched-induced apoptosis. Cancer Research. https://doi.org/10.1158/0008-5472.CAN-19-1340
Bissey PA, et al. Blocking SHH/Patched Interaction Triggers Tumor Growth Inhibition Through Patched-induced Apoptosis. Cancer Res. 2020 Feb 14; PubMed PMID: 32060146.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Blocking SHH/Patched interaction triggers tumor growth inhibition through Patched-induced apoptosis. AU - Bissey,Pierre-Antoine, AU - Mathot,Pauline, AU - Guix,Catherine, AU - Jasmin,Mélissa, AU - Goddard,Isabelle, AU - Costechareyre,Clélia, AU - Gadot,Nicolas, AU - Delcros,Jean-Guy, AU - Mali,Sachitanand M, AU - Fasan,Rudi, AU - Arrigo,André-Patrick, AU - Dante,Robert, AU - Ichim,Gabriel, AU - Mehlen,Patrick, AU - Fombonne,Joanna, Y1 - 2020/02/14/ PY - 2020/02/11/accepted PY - 2019/04/29/received PY - 2019/11/23/revised PY - 2020/2/16/entrez PY - 2020/2/16/pubmed PY - 2020/2/16/medline JF - Cancer research JO - Cancer Res. N2 - The Sonic Hedgehog (SHH) pathway plays a key role in cancer. Alterations of SHH canonical signaling, causally linked to tumor progression, have become rational targets for cancer therapy. However, Smoothened (Smo) inhibitors have failed to show clinical benefit in patients with cancers displaying SHH autocrine/paracrine expression. We reported earlier that the SHH receptor Patched (Ptc) is a dependence receptor that triggers apoptosis in the absence of SHH through a pathway that differs from the canonical one, thus generating a state of dependence on SHH for survival. Here, we propose a dual function for SHH: its binding to Ptc not only activates the SHH canonical pathway but also blocks Ptc-induced apoptosis. 80%, 64% and 8% of human colon, pancreatic and lung cancer cells, respectively, overexpressed SHH at transcriptional and protein levels. In addition, SHH-overexpressing cells expressed all the effectors of the Ptc-induced apoptotic pathway. While the canonical pathway remained unchanged, autocrine SHH interference in colon, pancreatic and lung cell lines triggered cell death through Ptc pro-apoptotic signaling. In vivo, SHH interference in colon cancer cell lines decreased primary tumor growth and metastasis. Therefore, the anti-tumor effect associated to SHH deprivation, usually thought to be a consequence of the inactivation of the canonical SHH pathway, is due to the engagement of Ptc pro-apoptotic activity. Together, these data strongly suggest that therapeutic strategies based on the disruption of SHH/Ptc interaction in SHH-overexpressing cancers should be explored. SN - 1538-7445 UR - https://www.unboundmedicine.com/medline/citation/32060146/Blocking_SHH/Patched_interaction_triggers_tumor_growth_inhibition_through_Patched-induced_apoptosis L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=32060146 DB - PRIME DP - Unbound Medicine ER -
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