Abstract

BackgroundThe tumor suppressor homeodomain-interacting protein kinase-2 (HIPK2) by phosphorylating serine 46 (Ser46) is a crucial regulator of p53 apoptotic function. HIPK2 is also a transcriptional co-repressor of hypoxia-inducible factor-1α (HIF-1α) restraining tumor angiogenesis and chemoresistance. HIPK2 can be deregulated in tumors by several mechanisms including hypoxia. Here, we sought to target hypoxia by restoring HIPK2 function and suppressing HIF-1α, in order to provide evidence for the involvement of both HIPK2 and p53 in counteracting hypoxia-induced chemoresistance.Methodology/Principal FindingsUpon exposure of colon and lung cancer cells to hypoxia, by either low oxygen or cobalt, HIPK2 function was impaired allowing for increased HIF-1α expression and inhibiting the p53-apoptotic response to drug. Cobalt suppressed HIPK2 recruitment onto HIF-1α promoter. Hypoxia induced expression of the p53 target MDM2 that downregulates HIPK2, thus MDM2 inhibition by siRNA restored the HIPK2/p53Ser46 response to drug. Zinc supplementation to hypoxia-treated cells increased HIPK2 protein stability and nuclear accumulation, leading to restoration of HIPK2 binding to HIF-1α promoter, repression of MDR1, Bcl2, and VEGF genes, and activation of the p53 apoptotic response to drug. Combination of zinc and ADR strongly suppressed tumor growth in vivo by inhibiting HIF-1 pathway and upregulating p53 apoptotic target genes.Conclusions/SignificanceWe show here for the first time that hypoxia-induced HIPK2 deregulation was counteracted by zinc that restored HIPK2 suppression of HIF-1 pathway and reactivated p53 apoptotic response to drug, underscoring the potential use of zinc supplementation in combination with chemotherapy to address hypoxia and improve tumor treatment.

Highlights

  • Solid tumors can survive hypoxic condition by using protective mechanisms including the activation of hypoxiainducible factor-1a (HIF-1a) a transcription factor that induces, among others, antiapoptotic Bcl2, multidrug resistance (MDR), VEGF gene expression, and reprogramming of glucose metabolism that account for cell proliferation, angiogenesis, and chemoresistance [1]

  • Homeodomain-interacting protein kinase-2 (HIPK2) is an important regulator of p53 apoptotic function, we have previously shown that homeodomain-interacting protein kinase-2 (HIPK2) phosphorylates p53 at serine 46 (Ser46) after severe DNA damage, inducing p53 specific apoptotic transcriptional activity [7,8,9]

  • The mechanistic explanation of hypoxia-induced chemoresistance involved upregulation of HIF-1 pathway and inhibition of the p53 pathway that were partly interconnected by the hypoxia-induced HIPK2 deregulation

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Summary

Introduction

Solid tumors can survive hypoxic condition (the high cell density of a tumor limits the availability of oxygen to cells) by using protective mechanisms including the activation of hypoxiainducible factor-1a (HIF-1a) a transcription factor that induces, among others, antiapoptotic Bcl, multidrug resistance (MDR), VEGF gene expression, and reprogramming of glucose metabolism that account for cell proliferation, angiogenesis, and chemoresistance [1]. Homeodomain-interacting protein kinase-2 (HIPK2) is an important regulator of p53 apoptotic function, we have previously shown that HIPK2 phosphorylates p53 at serine 46 (Ser46) after severe DNA damage, inducing p53 specific apoptotic transcriptional activity [7,8,9]. A major auto-regulatory, negative feed-back loop of p53 involves p53-dependent MDM2 induction that in turn binds and inactivates p53 by driving it to proteasomal degradation [12,13,14] In this regard, we have shown that HIPK2 neutralizes MDM2 inhibition rescuing p53 transcriptional activity and apoptotic function [15]. We sought to target hypoxia by restoring HIPK2 function and suppressing HIF-1a, in order to provide evidence for the involvement of both HIPK2 and p53 in counteracting hypoxia-induced chemoresistance

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