Modulation of bcl-2 family proteins in MAPK independent apoptosis induced by a cdc25 phosphatase inhibitor Cpd 5 in renal cancer cells

Ryuichi Mizuno, Mototsugu Oya, Satoshi Hara, Mayuko Matsumoto, Akio Horiguchi, Takashi Ohigashi, Ken Marumo, Masaru Murai

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Protein phosphatases have been classified into two basic types, namely protein serine/threonine phosphatase (PP), and protein tyrosine phosphatase (PTP). Cpd 5 is a selective inhibitor of cdc25 phosphatases, which belong to members of PTPs and regulate cell proliferation by controlling cyclin-dependent kinases (cdks). The present study was undertaken to investigate the potential utility of Cpd 5 as an anti-neoplastic agent for renal cell carcinomas (RCCs). Three renal cancer cell lines, 769P, Sw839, and A498 were used. The effects of Cpd 5 on the viability of renal cancer cell lines was analyzed using an Alamar Blue assay. Apoptosis was determined by flow cytometric TUNEL analysis. Changes in the expression of cdc25 phosphatases, mitogen-activated protein kinases (MAPKs), and bcl-2 family proteins were detected using Western blot analysis. The apoptosis-inducing effect of Cpd 5 on human RCC tissue was analyzed through TUNEL staining of organ cultures from RCCs. Cpd 5 showed a strong cytotoxicity against all renal cancer cell lines with an apoptosis-inducing effect. All cell lines treated with Cpd 5 resulted in a down-regulation of cdc25A, cdc25B, and cdc25C, however, the MAPK pathways were not affected. In addition, the up-regulation of bax, and the downregulation of bcl-2 and bcl-xL, was observed. In organ cultures from RCCs, TUNEL-positive apoptotic nuclei were observed when treated with Cpd 5. Cpd 5 was thus found to effectively inhibit the proliferation of human renal cancer cells while also inducing apoptosis by inhibiting cdc25 phosphatases and modulating bcl-2 family proteins. The administration of Cpd 5 may thus be an effective therapeutic approach for RCCs.

Original languageEnglish
Pages (from-to)639-644
Number of pages6
JournalOncology reports
Volume14
Issue number3
DOIs
Publication statusPublished - 2005 Sep

Keywords

  • Apoptosis
  • Bcl-2
  • Protein phosphatase inhibitor
  • Renal cell carcinoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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