Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer

Tulasigeri M. Totiger, Supriya Srinivasan, Venkatakrishna R. Jala, Purushottam Lamichhane, Austin R. Dosch, Alexander A. Gaidarski, Chandrashekhar Joshi, Shobith Rangappa, Jason Castellanos, Praveen Kumar Vemula, Xi Chen, Deukwoo Kwon, Nilesh Kashikar, Michael Vansaun, Nipun Merchant, Nagaraj Nagathihalli

Research output: Contribution to journalArticle

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy and is highly resistant to standard treatment regimens. Targeted therapies against KRAS, a mutation present in an overwhelming majority of PDAC cases, have been largely ineffective. However, inhibition of downstream components in the KRAS signaling cascade provides promising therapeutic targets in the management of PDAC and warrants further exploration. Here, we investigated Urolithin A (Uro A), a novel natural compound derived from pomegranates, which targets numerous kinases downstream of KRAS, in particular the PI3K/AKT/mTOR signaling pathways. We showed that treatment of PDAC cells with Uro A blocked the phosphorylation of AKT and p70S6K in vitro, successfully inhibited the growth of tumor xenografts, and increased overall survival of Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice compared with vehicle or gemcitabine therapy alone. Histologic evaluation of these Uro A-treated tumor samples confirmed mechanistic actions of Uro A via decreased phosphorylation of AKT and p70S6K, reduced proliferation, and increased cellular apoptosis in both xenograft and PKT mouse models. In addition, Uro A treatment reprogrammed the tumor microenvironment, as evidenced by reduced levels of infiltrating immunosuppressive cell populations such as myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Overall, this work provides convincing preclinical evidence for the utility of Uro A as a therapeutic agent in PDAC through suppression of the PI3K/AKT/mTOR pathway.

Original languageEnglish (US)
Pages (from-to)301-311
Number of pages11
JournalMolecular cancer therapeutics
Volume18
Issue number2
DOIs
StatePublished - Feb 1 2019

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Pancreatic Neoplasms
Phosphatidylinositol 3-Kinases
Adenocarcinoma
70-kDa Ribosomal Protein S6 Kinases
gemcitabine
Heterografts
Neoplasms
Phosphorylation
Tumor Microenvironment
Regulatory T-Lymphocytes
Therapeutics
Immunosuppressive Agents
3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one
Phosphotransferases
Macrophages
Cell Proliferation
Apoptosis
Mutation
Growth
Population

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer. / Totiger, Tulasigeri M.; Srinivasan, Supriya; Jala, Venkatakrishna R.; Lamichhane, Purushottam; Dosch, Austin R.; Gaidarski, Alexander A.; Joshi, Chandrashekhar; Rangappa, Shobith; Castellanos, Jason; Vemula, Praveen Kumar; Chen, Xi; Kwon, Deukwoo; Kashikar, Nilesh; Vansaun, Michael; Merchant, Nipun; Nagathihalli, Nagaraj.

In: Molecular cancer therapeutics, Vol. 18, No. 2, 01.02.2019, p. 301-311.

Research output: Contribution to journalArticle

Totiger, TM, Srinivasan, S, Jala, VR, Lamichhane, P, Dosch, AR, Gaidarski, AA, Joshi, C, Rangappa, S, Castellanos, J, Vemula, PK, Chen, X, Kwon, D, Kashikar, N, Vansaun, M, Merchant, N & Nagathihalli, N 2019, 'Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer', Molecular cancer therapeutics, vol. 18, no. 2, pp. 301-311. https://doi.org/10.1158/1535-7163.MCT-18-0464
Totiger, Tulasigeri M. ; Srinivasan, Supriya ; Jala, Venkatakrishna R. ; Lamichhane, Purushottam ; Dosch, Austin R. ; Gaidarski, Alexander A. ; Joshi, Chandrashekhar ; Rangappa, Shobith ; Castellanos, Jason ; Vemula, Praveen Kumar ; Chen, Xi ; Kwon, Deukwoo ; Kashikar, Nilesh ; Vansaun, Michael ; Merchant, Nipun ; Nagathihalli, Nagaraj. / Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer. In: Molecular cancer therapeutics. 2019 ; Vol. 18, No. 2. pp. 301-311.
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abstract = "Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy and is highly resistant to standard treatment regimens. Targeted therapies against KRAS, a mutation present in an overwhelming majority of PDAC cases, have been largely ineffective. However, inhibition of downstream components in the KRAS signaling cascade provides promising therapeutic targets in the management of PDAC and warrants further exploration. Here, we investigated Urolithin A (Uro A), a novel natural compound derived from pomegranates, which targets numerous kinases downstream of KRAS, in particular the PI3K/AKT/mTOR signaling pathways. We showed that treatment of PDAC cells with Uro A blocked the phosphorylation of AKT and p70S6K in vitro, successfully inhibited the growth of tumor xenografts, and increased overall survival of Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice compared with vehicle or gemcitabine therapy alone. Histologic evaluation of these Uro A-treated tumor samples confirmed mechanistic actions of Uro A via decreased phosphorylation of AKT and p70S6K, reduced proliferation, and increased cellular apoptosis in both xenograft and PKT mouse models. In addition, Uro A treatment reprogrammed the tumor microenvironment, as evidenced by reduced levels of infiltrating immunosuppressive cell populations such as myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Overall, this work provides convincing preclinical evidence for the utility of Uro A as a therapeutic agent in PDAC through suppression of the PI3K/AKT/mTOR pathway.",
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AU - Totiger, Tulasigeri M.

AU - Srinivasan, Supriya

AU - Jala, Venkatakrishna R.

AU - Lamichhane, Purushottam

AU - Dosch, Austin R.

AU - Gaidarski, Alexander A.

AU - Joshi, Chandrashekhar

AU - Rangappa, Shobith

AU - Castellanos, Jason

AU - Vemula, Praveen Kumar

AU - Chen, Xi

AU - Kwon, Deukwoo

AU - Kashikar, Nilesh

AU - Vansaun, Michael

AU - Merchant, Nipun

AU - Nagathihalli, Nagaraj

PY - 2019/2/1

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N2 - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy and is highly resistant to standard treatment regimens. Targeted therapies against KRAS, a mutation present in an overwhelming majority of PDAC cases, have been largely ineffective. However, inhibition of downstream components in the KRAS signaling cascade provides promising therapeutic targets in the management of PDAC and warrants further exploration. Here, we investigated Urolithin A (Uro A), a novel natural compound derived from pomegranates, which targets numerous kinases downstream of KRAS, in particular the PI3K/AKT/mTOR signaling pathways. We showed that treatment of PDAC cells with Uro A blocked the phosphorylation of AKT and p70S6K in vitro, successfully inhibited the growth of tumor xenografts, and increased overall survival of Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice compared with vehicle or gemcitabine therapy alone. Histologic evaluation of these Uro A-treated tumor samples confirmed mechanistic actions of Uro A via decreased phosphorylation of AKT and p70S6K, reduced proliferation, and increased cellular apoptosis in both xenograft and PKT mouse models. In addition, Uro A treatment reprogrammed the tumor microenvironment, as evidenced by reduced levels of infiltrating immunosuppressive cell populations such as myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Overall, this work provides convincing preclinical evidence for the utility of Uro A as a therapeutic agent in PDAC through suppression of the PI3K/AKT/mTOR pathway.

AB - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy and is highly resistant to standard treatment regimens. Targeted therapies against KRAS, a mutation present in an overwhelming majority of PDAC cases, have been largely ineffective. However, inhibition of downstream components in the KRAS signaling cascade provides promising therapeutic targets in the management of PDAC and warrants further exploration. Here, we investigated Urolithin A (Uro A), a novel natural compound derived from pomegranates, which targets numerous kinases downstream of KRAS, in particular the PI3K/AKT/mTOR signaling pathways. We showed that treatment of PDAC cells with Uro A blocked the phosphorylation of AKT and p70S6K in vitro, successfully inhibited the growth of tumor xenografts, and increased overall survival of Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice compared with vehicle or gemcitabine therapy alone. Histologic evaluation of these Uro A-treated tumor samples confirmed mechanistic actions of Uro A via decreased phosphorylation of AKT and p70S6K, reduced proliferation, and increased cellular apoptosis in both xenograft and PKT mouse models. In addition, Uro A treatment reprogrammed the tumor microenvironment, as evidenced by reduced levels of infiltrating immunosuppressive cell populations such as myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Overall, this work provides convincing preclinical evidence for the utility of Uro A as a therapeutic agent in PDAC through suppression of the PI3K/AKT/mTOR pathway.

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