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Monitoring Functionality and Morphology of Vasculature Recruited by Factors Secreted by Fast-growing Tumor-generating Cells
09:03

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Published on: November 23, 2014

Vascular targeting and antiangiogenesis agents induce drug resistance effector GRP78 within the tumor

Dezheng Dong1, Bryce Ko, Peter Baumeister

  • 1Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, California 90089-9176, USA.

Cancer Research
|July 5, 2005
PubMed

Insights

Targeting tumor blood vessels can cause glucose and oxygen deprivation, increasing GRP78 (glucose-regulated protein 78) expression. This may lead to drug resistance in breast cancer, but GRP78 suppression sensitizes cells to chemotherapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Tumor vascular targeting and antiangiogenesis therapies aim to inhibit tumor growth by limiting nutrient and oxygen supply.
  • These therapies can induce severe glucose and oxygen deprivation within tumors, potentially triggering adaptive prosurvival mechanisms.
  • Glucose-regulated protein 78 (GRP78), an endoplasmic reticulum chaperone, is upregulated by stress conditions like glucose depletion and anoxia.

Purpose of the Study:

  • To investigate the role of GRP78 in breast cancer response to antivascular and antiangiogenic therapies.
  • To determine if GRP78 overexpression contributes to drug resistance in human breast cancer.
  • To evaluate the therapeutic potential of suppressing GRP78 in combination with chemotherapy.

Main Methods:

  • Utilized a human breast cancer xenograft model treated with vascular targeting (combretastatin A4P) and antiangiogenic (contortrostatin) agents.
  • Assessed GRP78 promoter activity and protein levels in tumor cells.
  • Examined GRP78 expression in drug-resistant human breast cancer cell lines.
  • Employed lentiviral vectors expressing small interfering RNA (siRNA) to suppress GRP78 in cancer cells.

Main Results:

  • Treatment with combretastatin A4P or contortrostatin led to transcriptional activation of the Grp78 promoter and increased GRP78 protein levels in surviving tumor cells.
  • GRP78 was found to be overexpressed in human breast cancer cells resistant to various drug treatments.
  • Suppression of GRP78 using siRNA sensitized these cancer cells to etoposide-induced cell death.

Conclusions:

  • Antivascular and antiangiogenesis therapies can induce GRP78 expression in breast tumors due to severe glucose and oxygen deprivation.
  • Elevated GRP78 expression is associated with drug resistance in human breast cancer.
  • Targeting GRP78 may represent a viable strategy to overcome resistance and enhance chemotherapy efficacy in breast cancer treatment.

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