Tumor stressors induce two mechanisms of intracellular P-glycoprotein-mediated resistance that are overcome by lysosomal-targeted thiosemicarbazones

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Al-Akra, Lina
Bae, Dong-Hun
Sahni, Sumit
Huang, Michael LH
Park, Kyung Chan
Lane, Darius JR
Jansson, Patric J
Richardson, Des R
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2018
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https://creativecommons.org/licenses/by/4.0/
Abstract

Multidrug resistance (MDR) is a major obstacle in cancer treatment due to the ability of tumor cells to efflux chemotherapeutics via drug transporters (e.g. P-glycoprotein (Pgp; ABCB1)). Although the mechanism of Pgp-mediated drug efflux is known at the plasma membrane, the functional role of intracellular Pgp is unclear. Moreover, there has been intense focus on the tumor micro-environment as a target for cancer treatment. This investigation aimed to dissect the effects of tumor micro-environmental stress on subcellular Pgp expression, localization, and its role in MDR. These studies demonstrated that tumor microenvironment stressors (i.e. nutrient starvation, low glucose levels, reactive oxygen species, and hypoxia) induce Pgp-mediated drug resistance. This occurred by two mechanisms, where stressors induced 1) rapid Pgp internalization and redistribution via intracellular trafficking (within 1 h) and 2) hypoxia-inducible factor-1 expression after longer incubations (4 –24 h), which up-regulated Pgp and was accompanied by lysosomal biogenesis. These two mechanisms increased lysosomal Pgp and facilitated lysosomal accumulation of the Pgp substrate, doxorubicin, resulting in resistance. This was consistent with lysosomal Pgp being capable of transporting substrates into lysosomes. Hence, tumor micro-environmental stressors result in: 1) Pgp redistribution to lysosomes; 2) increased Pgp expression; 3) lysosomal biogenesis; and 4) potentiation of Pgp substrate transport into lysosomes. In contrast to doxorubicin, when stress stimuli increased lysosomal accumulation of the cytotoxic Pgp substrate, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), this resulted in the agent overcoming resistance. Overall, this investigation describes a novel approach to overcoming resistance in the stressful tumor micro-environment.

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Journal of Biological Chemistry
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293
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10
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© 2018 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Chemical sciences
Biological sciences
Biomedical and clinical sciences
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
ISONICOTINOYL HYDRAZONE CLASS
MULTIDRUG-RESISTANCE
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Al-Akra, L; Bae, D-H; Sahni, S; Huang, MLH; Park, KC; Lane, DJR; Jansson, PJ; Richardson, DR, Tumor stressors induce two mechanisms of intracellular P-glycoprotein-mediated resistance that are overcome by lysosomal-targeted thiosemicarbazones, Journal of Biological Chemistry, 2018, 293 (10), pp. 3562-3587
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