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Cited by 35Hedgehog Signaling Pathway StudiesPancreatic and Hepatic Oncology ResearchAutophagy in Disease and Therapy

Repurposing Niclosamide for Targeting Pancreatic Cancer by Inhibiting Hh/Gli Non-Canonical Axis of Gsk3β

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Kaushal, Jyoti, Bhatia, Rakesh, Kanchan, Ranjana, Raut, Pratima, Mallapragada, Surya, Ly, Quan, Batra, Surinder, Rachagani, Satyanarayana·2021·Cancers
DOI 10.3390/cancers13133105PMC PMC8269055
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Abstract

Niclosamide (Nic), an FDA-approved anthelmintic drug, is reported to have anti-cancer efficacy and is being assessed in clinical trials for various solid tumors. Based on its ability to target multiple signaling pathways, in the present study, we evaluated the therapeutic efficacy of Nic on pancreatic cancer (PC) in vitro. We observed an anti-cancerous effect of this drug as shown by the G0/G1 phase cell cycle arrest, inhibition of PC cell viability, colony formation, and migration. Our results revealed the involvement of mitochondrial stress and mTORC1-dependent autophagy as the predominant players of Nic-induced PC cell death. Significant reduction of Nic-induced reactive oxygen species (ROS) and cell death in the presence of a selective autophagy inhibitor spautin-1 demonstrated autophagy as a major contributor to Nic-mediated cell death. Mechanistically, Nic inhibited the interaction between BCL2 and Beclin-1 that supported the crosstalk of autophagy and apoptosis. Further, Nic treatment resulted in Gsk3β inactivation by phosphorylating its Ser-9 residue leading to upregulation of Sufu and Gli3, thereby negatively impacting hedgehog signaling and cell survival. Nic induced autophagic cell death, and p-Gsk3b mediated Sufu/Gli3 cascade was further confirmed by Gsk3β activator, LY-294002, by rescuing inactivation of Hh signaling upon Nic treatment. These results suggested the involvement of a non-canonical mechanism of Hh signaling, where p-Gsk3β acts as a negative regulator of Hh/Gli1 cascade and a positive regulator of autophagy-mediated cell death. Overall, this study established the therapeutic efficacy of Nic for PC by targeting p-Gsk3β mediated non-canonical Hh signaling and promoting mTORC1-dependent autophagy and cell death.

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  • Another antihelminthic drug, niclosamide, inhibited PARP cleavage in the presence of a late inhibitor of autophagy, Bafilomycin A1, in PDAC cells.

    “another antihelminthic drug niclosamide inhibited PARP cleavage in the presence of a late inhibitor of autophagy, Bafilomycin A1, in PDAC cells [48]”

    From Pyrvinium Pamoate Alone and With Gemcitabine Exhibits Anti‐Pancreatic Cancer Activity in <scp>2D</scp> and <scp>3D</scp> Cell Culture Models (2024) · cites this paper as [48]

    Results §3.2 reports increased cleaved PARP after niclosamide treatment in pancreatic cancer cells, not inhibition. Results §3.4 reports that the autophagy inhibitor spautin-1 attenuated niclosamide-induced apoptosis, but our copy does not report PARP cleavage in the presence of Bafilomycin A1. The specified drug combination and PARP outcome are therefore unsupported. (LLM, conf=0.86)

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Authors
Kaushal, J., Bhatia, R., Kanchan, R., Raut, P., Mallapragada, S., Ly, Q., Batra, S., & Rachagani, S.
Affiliations
  • University of Nebraska Medical Center (US)
  • Iowa State University (US)
Corresponding author
Rachagani, Satyanarayana
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2021-06-22
Volume
13
Issue
13
Pages
3105
ISSN
2072-6694 (ISSN-L)
DOI
10.3390/cancers13133105
PMC
PMC8269055
OpenAlex
W3173192835
Cited by
35
References
3
Citations by year
2026: 2 · 2025: 5 · 2024: 7 · 2023: 7 · 2022: 12 · 2021: 2
FWCI
2.20
Type
journal article
Language
en
Update notices
correction (2021-06-22)
Open access
Licence
Locations
  • Cancers (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DigitalCommons@UNMC (submittedVersion, cc-by)
  • Iowa State University Digital Repository (Iowa State University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Cancer Institute (CA247763; CA238953; CA217798; CA 228524; CA206444)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
niclosamide, pancreatic cancer, GSK3β phosphorylation, Gli3, SUFU, autophagy, mTORC1, autophagic cell death, mitochondrial stress, reactive oxygen species, drug repurposing

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Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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