p53 modulates the effect of ribosomal protein S6 kinase1 (S6K1) on cisplatin toxicity in chronic myeloid leukemia cells

Ling Yi Xiao, Wai-Ming Kan

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Chronic myeloid leukemia (CML) is characterized by the expression of the oncoprotein, BCR-ABL. BCR-ABL inhibitors revolutionized CML chemotherapy while blast crisis (BC) CML patients are less responsive. Since suppression of ribosomal protein S6 kinase1 (S6K1) phosphorylation reverses the resistance to BCR-ABL inhibitor in CML cells and S6K1 inhibitors augment cisplatin toxicity in lung cancer cells, we speculated that combination of S6K1 inhibitor and cisplatin may be beneficial for eliminating BC CML cells. To our surprise, S6K1 inhibition decreased cisplatin-induced DNA damage and cell death only in p53-/− BC CML cells but not in p53+/+ BC CML cells. During the progression of CML, p53 expression either decreases or mutates. Moreover, the expression of p53 affects drug response of CML cells. Our results confirmed that S6K1 inhibition reversed cisplatin toxicity is dependent on p53 expression in CML cells. Moreover, p53 attenuated the phosphorylation and localization of S6K1 via attenuating 3-phosphoinositide dependent protein kinase-1 (PDK1) phosphorylation. Furthermore, S6K1 acts via DNA-PKcs to regulate H2AX phosphorylation and PARP cleavage, respectively. Taken together, our results suggest that p53/PDK1/S6K1 is a novel pathway regulating cisplatin toxicity in BC CML cells.

Original languageEnglish
Pages (from-to)443-462
Number of pages20
JournalPharmacological Research
Volume119
DOIs
Publication statusPublished - 2017 May 1

Fingerprint

Ribosomal Protein S6
Myeloid Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Cisplatin
S 6
Blast Crisis
Phosphorylation
3-Phosphoinositide-Dependent Protein Kinases
Oncogene Proteins
Phosphatidylinositols
Protein Kinases
DNA Damage
Lung Neoplasms

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

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abstract = "Chronic myeloid leukemia (CML) is characterized by the expression of the oncoprotein, BCR-ABL. BCR-ABL inhibitors revolutionized CML chemotherapy while blast crisis (BC) CML patients are less responsive. Since suppression of ribosomal protein S6 kinase1 (S6K1) phosphorylation reverses the resistance to BCR-ABL inhibitor in CML cells and S6K1 inhibitors augment cisplatin toxicity in lung cancer cells, we speculated that combination of S6K1 inhibitor and cisplatin may be beneficial for eliminating BC CML cells. To our surprise, S6K1 inhibition decreased cisplatin-induced DNA damage and cell death only in p53-/− BC CML cells but not in p53+/+ BC CML cells. During the progression of CML, p53 expression either decreases or mutates. Moreover, the expression of p53 affects drug response of CML cells. Our results confirmed that S6K1 inhibition reversed cisplatin toxicity is dependent on p53 expression in CML cells. Moreover, p53 attenuated the phosphorylation and localization of S6K1 via attenuating 3-phosphoinositide dependent protein kinase-1 (PDK1) phosphorylation. Furthermore, S6K1 acts via DNA-PKcs to regulate H2AX phosphorylation and PARP cleavage, respectively. Taken together, our results suggest that p53/PDK1/S6K1 is a novel pathway regulating cisplatin toxicity in BC CML cells.",
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p53 modulates the effect of ribosomal protein S6 kinase1 (S6K1) on cisplatin toxicity in chronic myeloid leukemia cells. / Xiao, Ling Yi; Kan, Wai-Ming.

In: Pharmacological Research, Vol. 119, 01.05.2017, p. 443-462.

Research output: Contribution to journalArticle

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