Suppression of human tumor cell proliferation through mitochondrial targeting

Ekhson Holmuhamedov, Lionel Lewis, Martin Bienengraeber, Madina Holmuhamedova, Arshad Jahangir, Andre Terzic

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Intracellular calcium signaling plays a central role in cell proliferation. In leukemic cells, the calcium release-activated calcium channels provide a major pathway for calcium entry (ICRAC) perpetuating progression through the cell cycle. Although ICRAC is under mitochondrial regulation, targeting mitochondrial function has not been exploited to control malignant cell growth. The benzothiadiazine diazoxide, which depolarized respiration-dependent mitochondrial membrane potential, reduced the rate of proliferation and arrested human acute leukemic T cells in the G0/G1 phase. Diazoxide did not alter cellular energetics, but rather inhibited the mitochondria-controlled ICRAC and reduced calcium influx into tumor cells. The antiproliferative action of diazoxide was mimicked by removal of extracellular calcium or by the tyrphostin A9, an ICRAC inhibitor. Deletion of the mitochondrial genome, which encodes essential respiratory chain enzyme subunits, attenuated the inhibitory effect of diazoxide on ICRAC-mediated calcium influx and cell proliferation. Thus, manipulation of mitochondrial function and associated calcium signaling provides a basis for a novel anticancer strategy.-Holmuhamedov, E., Lewis, L., Bienengraeber, M., Holmuhamedova, M., Jahangir, A., Terzic, A. Suppression of human tumor cell proliferation through mitochondrial targeting.

Original languageEnglish (US)
Pages (from-to)1010-1016
Number of pages7
JournalFASEB Journal
Volume16
Issue number9
DOIs
StatePublished - 2002

Keywords

  • Calcium release-activated calcium channels
  • Cancer
  • Diazoxide
  • Mitochondrial DNA

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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