Hpr6 (heme-1 domain protein) regulates the susceptibility of cancer cells to chemotherapeutic drugs

Gerard Crudden, Rachel E. Chitti, Rolf J. Craven

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Cancer cells have varying levels of susceptibility to chemotherapeutic agents, and the proteins that direct drug susceptibility are promising targets for intervention in cancer. Hpr6 (heme-1 domain protein)/PGRMC1 (progesterone receptor membrane component 1) is overexpressed in tumors, and Hpr6 is the human homolog of a budding yeast damage resistance gene called Dap1p. Cells lacking Dap1p are damage-sensitive, and we have found that inhibition of Hpr6 expression by RNA inhibition (RNAi) increases sensitivity of breast cancer cells to chemotherapeutic drugs. Hpr6 is composed largely of a cytochrome b 5-related heme-1 domain, and we have found that purified Hpr6 binds to heme, similar to its yeast and rodent homologues. We generated an aspartate 120-to-glycine (D120G) mutant of Hpr6 at a highly conserved site in the heme-1 domain and demonstrated that Hpr6-D120G cannot bind to heme. The Hpr6-D120G mutant was named Hpr6hbd for heme binding defective. We prepared an adenovirus encoding Hpr6hbd and found that adenovirus Hpr6 hbd increases susceptibility of breast cancer cells to doxorubicin and camptothecin. Our findings support a model in which Hpr6, similar to its yeast homolog, binds to heme and regulates susceptibility to damaging agents.

Original languageEnglish
Pages (from-to)448-455
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume316
Issue number1
DOIs
StatePublished - Jan 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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