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Sensitization of hepatocellular carcinoma cells towards doxorubicin and sorafenib is facilitated by glucose-dependent alterations in reactive oxygen species, P-glycoprotein and DKK4

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Abstract

Altered glucose uptake and metabolism is the key characteristic of cancer cells including hepatocellular carcinoma (HCC). However, role of glucose availability in chemotherapeutic outcome of HCC is unclear. The present study investigates the effect of glucose facilitated sensitization of HCC cells towards doxorubicin (DOX) and sorafenib (SORA). In HCC cells, we observed that hyperglycemic culture condition (HG) is associated with increased sensitivity towards DOX and SORA. P-glycoprotein (P-gp), a transporter involved in drug efflux, was elevated in HCC cells in NG, rendering them less susceptible to DOX and SORA. Further, this study demonstrated that knockdown of dickkopf protein 4 (DKK4), a Wnt antagonist protein, causes enhanced glucose uptake and reduction in P-gp level rendering HCC cells in NG sensitive to DOX and SORA. Moreover, HG elevates the level of intracellular reactive oxygen species (ROS), which regulates P-gp. Alteration in intracellular ROS did not directly affect regulation of DKK4 in HCC cells. Functional assays suggest that alterations in DKK4 and P-gp level in HCC cells are dependent on glucose availability and changes in ROS level because of enhanced glucose utilization, respectively. Collectively, the present study highlights direct involvement of glucose-induced ROS, DKK4 and P-gp in altering the sensitivity of HCC cells towards DOX and SORA.

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Abbreviations

CytoB:

cytochalasin B

DKK4:

dickkopf protein 4

DOX:

doxorubicin

HCC:

hepatocellular carcinoma

HG:

hyperglycemic culture condition

NG:

normoglycemic culture condition

P-gp:

P-glycoprotein

ROS:

intracellular reactive oxygen species

SORA:

sorafenib

VPL:

verapamil

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Acknowledgements

The authors thank Dr. S.C. Mande, Director, NCCS, Pune, India, for being very supportive and giving all the encouragement to perform this work. SC thanks Council for Scientific and Industrial Research (CSIR), India. SS and PR thank University Grants Commission (UGC), New Delhi, India, and DA thanks Department of Biotechnology (DBT), India for the research fellowship. MV thanks Amrita Vishwa Vidyapeetham, Clappana, Kollam, Kerala, India, for the research fellowship. The support from Central Instrumental Facility and technical staff of NCCS is duly acknowledged. The authors acknowledge Amrita Agilent Analytical Research Centre for the MS data collection and analysis.

Funding

This work was supported by intramural grant from NCCS funded by the Department of Biotechnology, Government of India and internal funding from Amrita Vishwa Vidyapeetham.

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Authors and Affiliations

  1. National Centre for Cell Science, Savitribai Phule Pune University Campus, Pune, 411 007, India

    Surbhi Chouhan, Snahlata Singh, Dipti Athavale, Pranay Ramteke & Manoj Kumar Bhat

  2. Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Clappana P.O, Kollam, 690 525, India

    Muralidharan Vanuopadath, Bipin G Nair & Sudarslal Sadasivan Nair

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  1. Surbhi Chouhan
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  2. Snahlata Singh
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Correspondence to Manoj Kumar Bhat.

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Chouhan, S., Singh, S., Athavale, D. et al. Sensitization of hepatocellular carcinoma cells towards doxorubicin and sorafenib is facilitated by glucose-dependent alterations in reactive oxygen species, P-glycoprotein and DKK4. J Biosci 45, 97 (2020). https://doi.org/10.1007/s12038-020-00065-y

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