Regulation of human monocarboxylate transporter 4 in skeletal muscle cells: the role of protein kinase C (PKC)

Int J Pharm. 2012 May 30;428(1-2):25-32. doi: 10.1016/j.ijpharm.2012.02.021. Epub 2012 Mar 9.


In the present study, to clarify the role of protein kinase C (PKC) in the regulation of monocarboxylate transporter 4 (MCT4) expression, we examined the regulation mechanism of MCT4 expression in human rhabdomyosarcoma (RD) cells, an in vitro skeletal muscle model. Exposure of RD cells to PMA, a PKC activator, for 24 h resulted in a two-fold increase in the amount of lactic acid in the growth medium. In parallel to an increase in lactic acid release from RD cells, the level of MCT4 mRNA and protein were also significantly increased in RD cells. A PKC inhibitory study indicated that PMA-induced stimulation of MCT4 expression can be mediated through a novel PKC isoform, especially PKCδ. Moreover, rottlerin, a selective PKCδ inhibitor, decreased PMA-induced MCT4 promoter activity. Deletion and mutational analysis suggested that the potential hypoxia-response elements (HREs) played a major role in the observed modulation of MCT4 expression by PMA. Furthermore, we found that small interfering RNA (siRNA)-mediated knockdown of hypoxia-inducible factor 1α (HIF-1α) significantly inhibited PMA-induced MCT4 promoter activity. Our results show that the effects of PMA on MCT4 expression are mediated through an indirect pathway partially involving PKCδ and HIF-1α transcription factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetophenones / pharmacology
  • Base Sequence
  • Benzopyrans / pharmacology
  • Humans
  • Hypoxia / genetics
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Lactic Acid / metabolism
  • Molecular Sequence Data
  • Monocarboxylic Acid Transporters / genetics
  • Monocarboxylic Acid Transporters / metabolism*
  • Muscle Cells / drug effects
  • Muscle Cells / enzymology
  • Muscle Cells / metabolism*
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / enzymology
  • Muscle, Skeletal / metabolism*
  • Promoter Regions, Genetic / drug effects
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • RNA, Messenger / genetics
  • Response Elements / drug effects
  • Rhabdomyosarcoma / enzymology
  • Rhabdomyosarcoma / genetics
  • Rhabdomyosarcoma / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic / drug effects
  • Tumor Cells, Cultured


  • Acetophenones
  • Benzopyrans
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Monocarboxylic Acid Transporters
  • Muscle Proteins
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • SLC16A4 protein, human
  • Transcription Factors
  • Lactic Acid
  • rottlerin
  • Protein Kinase C