Overexpression of retinoic acid receptor beta induces growth arrest and apoptosis in oral cancer cell lines

Jpn J Cancer Res. 2001 Jan;92(1):42-50. doi: 10.1111/j.1349-7006.2001.tb01046.x.

Abstract

Expression of retinoic acid receptor beta (RARbeta) is reported to be absent or down-regulated in oral squamous cell carcinomas. Recently, we found that the growth-inhibitory effect of 9-cis-retinoic acid (9CRA) on oral squamous cell carcinoma may depend on the expression levels of endogenous RARbeta. In order to clarify the role of RARbeta in growth and differentiation, we transfected RARbeta expression vector into oral squamous carcinoma cell lines, HSC-4 and Ho-1-N-1. Both RARbeta-transfected cell lines displayed growth inhibition. Moreover, RARbeta-transfected clones underwent morphological changes, and RARbeta-transfected HSC-4 clones underwent apoptosis even in the absence of 9CRA treatment. In contrast, RARbeta-transfected Ho-1-N-1 clones exhibited cell cycle arrest without undergoing apoptosis initially; however, apoptosis was induced in these cells after 6 days of 9CRA treatment. RARalpha and RARgamma expression was reduced at both the protein and mRNA levels in RARbeta transfectants, whereas the expression of retinoid X receptor alpha (RXRalpha) was not altered. RARb transfectants exhibited alterations in the levels of cell cycle-associated proteins, histone acetyltransferase (HAT) and apoptosis-associated proteins. After 6 days of 9CRA treatment, RARbeta transfectants overexpressed Waf1 / Cip1 / Sdi1 / p21, Kip1 / p27, chk1, p300 / CBP, BAX, Bak, Apaf 1, caspase 3 and caspase 9. Conversely, E2F1, cdc25B and HDAC1 were down-regulated in these transfectants. In addition, histone H4 acetylation was induced in RARb transfectants. These findings suggest that histone acetylation mediated by histone acetyltransferase and p300 / CBP may play a role in the growth arrest and apoptosis induced by RARbeta transfection in oral squamous cell carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alitretinoin
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / physiopathology
  • Cell Cycle / drug effects*
  • Cell Division / drug effects
  • Humans
  • Mouth Neoplasms / drug therapy
  • Mouth Neoplasms / metabolism*
  • Mouth Neoplasms / physiopathology
  • Neoplasm Proteins / metabolism
  • RNA, Messenger / metabolism
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism*
  • Retinoic Acid Receptor alpha
  • Transfection
  • Tretinoin / pharmacology*
  • Tumor Cells, Cultured / drug effects

Substances

  • Antineoplastic Agents
  • Neoplasm Proteins
  • RARA protein, human
  • RNA, Messenger
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • retinoic acid receptor beta
  • Alitretinoin
  • Tretinoin