Attenuation of PTEN increases p21 stability and cytosolic localization in kidney cancer cells: A potential mechanism of apoptosis resistance

Pei Yin Lin, Susan P. Fosmire, See Hyoung Park, Jin Young Park, Shairaz Baksh, Jaime F. Modiano, Robert H Weiss

Research output: Contribution to journalArticle

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Abstract

Background: The PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten) tumor suppressor gene is frequently mutated or deleted in a wide variety of solid tumors, and these cancers are generally more aggressive and difficult to treat than those possessing wild type PTEN. While PTEN lies upstream of the phosphoinositide-3 kinase signaling pathway, the mechanisms that mediate its effects on tumor survival remain incompletely understood. Renal cell carcinoma (RCC) is associated with frequent treatment failures (∼90% in metastatic cases), and these tumors frequently contain PTEN abnormalities. Results: Using the ACHN cell line containing wild type PTEN, we generated a stable PTEN knockdown RCC cell line using RNA interference. We then used this PTEN knockdown cell line to show that PTEN attenuation increases resistance to cisplatin-induced apoptosis, a finding associated with increased levels of the cyclin kinase inhibitor p21. Elevated levels of p21 result from stabilization of the protein, and they are dependent on the activities of phosphoinositide-3 kinase and Akt. More specifically, the accumulation of p21 occurs preferentially in the cytosolic compartment, which likely contributes to both cell cycle progression and resistance to apoptosis. Conclusion: Since p21 regulates a decision point between repair and apoptosis after DNA damage, our data suggest that p21 plays a key role in mechanisms used by PTEN-deficient tumors to escape chemotherapy. This in turn raises the possibility to use p21 attenuators as chemotherapy sensitizers, an area under active continuing investigation in our laboratories.

Original languageEnglish (US)
Article number16
JournalMolecular Cancer
Volume6
DOIs
StatePublished - 2007

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Kidney Neoplasms
Tumors
Cells
Apoptosis
1-Phosphatidylinositol 4-Kinase
Renal Cell Carcinoma
Cell Line
Chemotherapy
Neoplasms
Phosphatidylinositols
PTEN Phosphohydrolase
Cyclin-Dependent Kinase Inhibitor p21
Tumor Escape
Drug Therapy
Phosphotransferases
RNA Interference
Tumor Suppressor Genes
Treatment Failure
Cisplatin
DNA Damage

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)
  • Cancer Research
  • Molecular Medicine

Cite this

Attenuation of PTEN increases p21 stability and cytosolic localization in kidney cancer cells : A potential mechanism of apoptosis resistance. / Lin, Pei Yin; Fosmire, Susan P.; Park, See Hyoung; Park, Jin Young; Baksh, Shairaz; Modiano, Jaime F.; Weiss, Robert H.

In: Molecular Cancer, Vol. 6, 16, 2007.

Research output: Contribution to journalArticle

Lin, Pei Yin ; Fosmire, Susan P. ; Park, See Hyoung ; Park, Jin Young ; Baksh, Shairaz ; Modiano, Jaime F. ; Weiss, Robert H. / Attenuation of PTEN increases p21 stability and cytosolic localization in kidney cancer cells : A potential mechanism of apoptosis resistance. In: Molecular Cancer. 2007 ; Vol. 6.
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abstract = "Background: The PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten) tumor suppressor gene is frequently mutated or deleted in a wide variety of solid tumors, and these cancers are generally more aggressive and difficult to treat than those possessing wild type PTEN. While PTEN lies upstream of the phosphoinositide-3 kinase signaling pathway, the mechanisms that mediate its effects on tumor survival remain incompletely understood. Renal cell carcinoma (RCC) is associated with frequent treatment failures (∼90{\%} in metastatic cases), and these tumors frequently contain PTEN abnormalities. Results: Using the ACHN cell line containing wild type PTEN, we generated a stable PTEN knockdown RCC cell line using RNA interference. We then used this PTEN knockdown cell line to show that PTEN attenuation increases resistance to cisplatin-induced apoptosis, a finding associated with increased levels of the cyclin kinase inhibitor p21. Elevated levels of p21 result from stabilization of the protein, and they are dependent on the activities of phosphoinositide-3 kinase and Akt. More specifically, the accumulation of p21 occurs preferentially in the cytosolic compartment, which likely contributes to both cell cycle progression and resistance to apoptosis. Conclusion: Since p21 regulates a decision point between repair and apoptosis after DNA damage, our data suggest that p21 plays a key role in mechanisms used by PTEN-deficient tumors to escape chemotherapy. This in turn raises the possibility to use p21 attenuators as chemotherapy sensitizers, an area under active continuing investigation in our laboratories.",
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