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

6 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
Publication statusPublished - 2005 Sep

Fingerprint

cdc25 Phosphatases
Mitogen-Activated Protein Kinases
Renal Cell Carcinoma
Apoptosis
Kidney Neoplasms
In Situ Nick-End Labeling
Cell Line
Proteins
Phosphoprotein Phosphatases
Organ Culture Techniques
Down-Regulation
Protein Tyrosine Phosphatases
Cyclin-Dependent Kinases
Mitogen-Activated Protein Kinase 1
Up-Regulation
Western Blotting
Cell Proliferation
Staining and Labeling

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Modulation of bcl-2 family proteins in MAPK independent apoptosis induced by a cdc25 phosphatase inhibitor Cpd 5 in renal cancer cells. / Mizuno, Ryuichi; Oya, Mototsugu; Hara, Satoshi; Matsumoto, Mayuko; Horiguchi, Akio; Ohigashi, Takashi; Marumo, Ken; Murai, Masaru.

In: Oncology Reports, Vol. 14, No. 3, 09.2005, p. 639-644.

Research output: Contribution to journalArticle

Mizuno, R, Oya, M, Hara, S, Matsumoto, M, Horiguchi, A, Ohigashi, T, Marumo, K & Murai, M 2005, 'Modulation of bcl-2 family proteins in MAPK independent apoptosis induced by a cdc25 phosphatase inhibitor Cpd 5 in renal cancer cells', Oncology Reports, vol. 14, no. 3, pp. 639-644.
Mizuno, Ryuichi ; Oya, Mototsugu ; Hara, Satoshi ; Matsumoto, Mayuko ; Horiguchi, Akio ; Ohigashi, Takashi ; Marumo, Ken ; Murai, Masaru. / Modulation of bcl-2 family proteins in MAPK independent apoptosis induced by a cdc25 phosphatase inhibitor Cpd 5 in renal cancer cells. In: Oncology Reports. 2005 ; Vol. 14, No. 3. pp. 639-644.
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AU - Marumo, Ken

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AB - 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.

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