Zinc-doped copper oxide nanocomposites inhibit the growth of pancreatic cancer by inducing autophagy through AMPK/mTOR pathway

Xiao Li; Huanli Xu; Cong Li; Gan Qiao; Ammad Ahmad Farooqi; Aharon Gedanken; Xiaohui Liu; Xiukun Lin

doi:10.3389/fphar.2019.00319

Zinc-doped copper oxide nanocomposites inhibit the growth of pancreatic cancer by inducing autophagy through AMPK/mTOR pathway

Xiao Li, Huanli Xu, Cong Li, Gan Qiao, Ammad Ahmad Farooqi, Aharon Gedanken, Xiaohui Liu, Xiukun Lin

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

Abstract

Zinc doped copper oxide nanocomposites (Zn-CuO NPs) is a novel doped metal nanomaterial synthesized by our group using the sonochemical method. Our previous studies have shown that Zn-CuO NPs could inhibit cancer cell proliferation by inducing apoptosis via ROS-mediated pathway. In the present study, we studied the anticancer effect of Zn-CuO NPs on human pancreatic cancer cells. MTS assay revealed that Zn-CuO NPs was able to inhibit cancer cell growth. TEM, flow cytometry and fluorescence microscope analysis showed that Zn-CuO NPs induced autophagy significantly; the number of autophagosomes increased obviously in cells treated with Zn-CuO NPs. Western blot analysis revealed that treatment with the NPs resulted in activation of AMPK/mTOR pathway in both AsPC-1 and MIA Paca-2 cells in dose dependent manners. Moreover, in the presence of AMPK activator AMPKinone, the protein level of p-AMPK, p-ULK1, Beclin-1 and LC3-II/LC3-I increased, while the protein expression of p-AMPK, p-ULK1, Beclin-1 and LC3-II/LC3-I decreased in the presence of AMPK inhibitor Compound C. In vivo study using xenograft mice revealed that Zn-CuO NPs significantly inhibited tumor growth with low toxicity. Our study confirms that Zn-CuO NPs inhibit the tumor growth both in vitro and in vivo for pancreatic cancer. AMPK/mTOR pathway plays an important role in the NPs induced inhibition of tumor growth.

Original language	English
Article number	319
Journal	Frontiers in Pharmacology
Volume	10
Issue number	APR
DOIs	https://doi.org/10.3389/fphar.2019.00319
State	Published - 2019

Bibliographical note

Publisher Copyright:
© 2019 Li, Xu, Li, Qiao, Farooqi, Gedanken, Liu and Lin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Funding

The study was supported by the National Natural Science Foundation of China (# 81573457 and 81773776). The present study was also supported in part by grants from the National Innovative Drug Development Projects of China (# 2014ZX-09102043-001). We are also grateful for the support of the Department of Science and Technology in Shandong Province of China (No#: 2016GSF201183, ZR2017MH117, and 2018YYSP025, ZR2017MH027), Zibo Development Program of Science and Technology, in Shandong, China (2016kj100048), and Sichuan Science and Technology Department, China (# 2017HH0104 and 17GJHZ0074).

Funders	Funder number
National Innovative Drug Development Projects of China	2014ZX-09102043-001
Sichuan Science and Technology Department, China	17GJHZ0074, 2017HH0104
Department of Science and Technology of Shandong Province	ZR2017MH027, 2016GSF201183, 2016kj100048, 2018YYSP025, ZR2017MH117
National Natural Science Foundation of China	81773776, 81573457

Keywords

AMPK
Autophagy
In vivo activity
Pancreatic cancer
Zinc doped copper oxide nanocomposites

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3389/fphar.2019.00319

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abstract = "Zinc doped copper oxide nanocomposites (Zn-CuO NPs) is a novel doped metal nanomaterial synthesized by our group using the sonochemical method. Our previous studies have shown that Zn-CuO NPs could inhibit cancer cell proliferation by inducing apoptosis via ROS-mediated pathway. In the present study, we studied the anticancer effect of Zn-CuO NPs on human pancreatic cancer cells. MTS assay revealed that Zn-CuO NPs was able to inhibit cancer cell growth. TEM, flow cytometry and fluorescence microscope analysis showed that Zn-CuO NPs induced autophagy significantly; the number of autophagosomes increased obviously in cells treated with Zn-CuO NPs. Western blot analysis revealed that treatment with the NPs resulted in activation of AMPK/mTOR pathway in both AsPC-1 and MIA Paca-2 cells in dose dependent manners. Moreover, in the presence of AMPK activator AMPKinone, the protein level of p-AMPK, p-ULK1, Beclin-1 and LC3-II/LC3-I increased, while the protein expression of p-AMPK, p-ULK1, Beclin-1 and LC3-II/LC3-I decreased in the presence of AMPK inhibitor Compound C. In vivo study using xenograft mice revealed that Zn-CuO NPs significantly inhibited tumor growth with low toxicity. Our study confirms that Zn-CuO NPs inhibit the tumor growth both in vitro and in vivo for pancreatic cancer. AMPK/mTOR pathway plays an important role in the NPs induced inhibition of tumor growth.",

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author = "Xiao Li and Huanli Xu and Cong Li and Gan Qiao and Farooqi, {Ammad Ahmad} and Aharon Gedanken and Xiaohui Liu and Xiukun Lin",

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AU - Qiao, Gan

AU - Farooqi, Ammad Ahmad

AU - Gedanken, Aharon

AU - Liu, Xiaohui

AU - Lin, Xiukun

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PY - 2019

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N2 - Zinc doped copper oxide nanocomposites (Zn-CuO NPs) is a novel doped metal nanomaterial synthesized by our group using the sonochemical method. Our previous studies have shown that Zn-CuO NPs could inhibit cancer cell proliferation by inducing apoptosis via ROS-mediated pathway. In the present study, we studied the anticancer effect of Zn-CuO NPs on human pancreatic cancer cells. MTS assay revealed that Zn-CuO NPs was able to inhibit cancer cell growth. TEM, flow cytometry and fluorescence microscope analysis showed that Zn-CuO NPs induced autophagy significantly; the number of autophagosomes increased obviously in cells treated with Zn-CuO NPs. Western blot analysis revealed that treatment with the NPs resulted in activation of AMPK/mTOR pathway in both AsPC-1 and MIA Paca-2 cells in dose dependent manners. Moreover, in the presence of AMPK activator AMPKinone, the protein level of p-AMPK, p-ULK1, Beclin-1 and LC3-II/LC3-I increased, while the protein expression of p-AMPK, p-ULK1, Beclin-1 and LC3-II/LC3-I decreased in the presence of AMPK inhibitor Compound C. In vivo study using xenograft mice revealed that Zn-CuO NPs significantly inhibited tumor growth with low toxicity. Our study confirms that Zn-CuO NPs inhibit the tumor growth both in vitro and in vivo for pancreatic cancer. AMPK/mTOR pathway plays an important role in the NPs induced inhibition of tumor growth.

AB - Zinc doped copper oxide nanocomposites (Zn-CuO NPs) is a novel doped metal nanomaterial synthesized by our group using the sonochemical method. Our previous studies have shown that Zn-CuO NPs could inhibit cancer cell proliferation by inducing apoptosis via ROS-mediated pathway. In the present study, we studied the anticancer effect of Zn-CuO NPs on human pancreatic cancer cells. MTS assay revealed that Zn-CuO NPs was able to inhibit cancer cell growth. TEM, flow cytometry and fluorescence microscope analysis showed that Zn-CuO NPs induced autophagy significantly; the number of autophagosomes increased obviously in cells treated with Zn-CuO NPs. Western blot analysis revealed that treatment with the NPs resulted in activation of AMPK/mTOR pathway in both AsPC-1 and MIA Paca-2 cells in dose dependent manners. Moreover, in the presence of AMPK activator AMPKinone, the protein level of p-AMPK, p-ULK1, Beclin-1 and LC3-II/LC3-I increased, while the protein expression of p-AMPK, p-ULK1, Beclin-1 and LC3-II/LC3-I decreased in the presence of AMPK inhibitor Compound C. In vivo study using xenograft mice revealed that Zn-CuO NPs significantly inhibited tumor growth with low toxicity. Our study confirms that Zn-CuO NPs inhibit the tumor growth both in vitro and in vivo for pancreatic cancer. AMPK/mTOR pathway plays an important role in the NPs induced inhibition of tumor growth.

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Zinc-doped copper oxide nanocomposites inhibit the growth of pancreatic cancer by inducing autophagy through AMPK/mTOR pathway

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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