Reference Detail

Ref Type

Journal Article

PMID

(22862161)

Authors

Slovackova J, Smarda J, Smardova J

Title

Roscovitine-induced apoptosis of H1299 cells depends on functional status of p53.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Neoplasma	59	6	2012	606-12	Neoplasma

URL

Abstract Text

Roscovitine, an inhibitor of cyclin-dependent kinases, is promising anticancer agent. Its antiproliferative and cytotoxic effects can be mediated by the p53 signaling pathway. To define the role of p53 in roscovitine-induced cell response, we prepared H1299/p53 cell lines inducibly expressing specific variants of p53 (p53wt and hotspot R175H, temperature-dependent P98A, A159V, S215G, Y220C, Y234C mutants). In the presence of roscovitine, each cell line variant behaved in specific way reflecting activity of the p53 protein. Roscovitine decreased production of the cell cycle inhibitor p21 and induced apoptosis. This effect was the most efficient in cells expressing p53wt protein with full activity. The cell expressing partially and conditionally active p53 mutants responded to roscovitine less efficiently. The cells expressing p53 mutants A159V and Y234C were very sensitive to roscovitine but their response was clearly temperature-dependent. The cells expressing P98A, S215G and Y220C p53 mutants exhibited only weak sensitivity to roscovitine and underwent apoptosis in low frequency. In principle, each td p53 mutant responded to roscovitine in distinct way. We showed clearly that the impact of roscovitine on H1299 cells depends on functional status of p53 they produce. This suggests that patients with tumors exhibiting specific p53 variants can benefit from the roscovitine therapy.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description
TP53	A159V	missense	loss of function	TP53 A159V lies within the DNA-binding domain of the Tp53 protein (PMID: 15510160). A159V results decreased Tp53 transactivation activity and leads to reduced apoptosis relative to wild type Tp53 in cell culture (PMID: 22862161).
TP53	P98A	missense	loss of function	TP53 P98A lies within the CCAR2 and WWOX-interacting regions of the Tp53 protein (UniProt.org). P98A results in decreased Tp53 transactivation activity and leads to reduced apoptosis relative to wild-type Tp53 in cell culture (PMID: 22862161, PMID: 20505364).
TP53	S215G	missense	loss of function	TP53 S215G lies within the DNA-binding domain of the Tp53 protein (PMID: 15510160). S215G results in decreased Tp53 transactivation activity and leads to reduced apoptosis relative to wild type Tp53 in cell culture (PMID: 22862161).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 A159V	lung non-small cell carcinoma	decreased response	Seliciclib	Preclinical - Cell culture	Actionable	In a preclinical study, non-small cell lung carcinoma cells overexpressing TP53 A159V demonstrated reduced sensitivity to Roscovotine (seliciclib) induced apoptosis in culture (PMID: 22862161).	22862161
TP53 P98A	lung non-small cell carcinoma	decreased response	Seliciclib	Preclinical - Cell culture	Actionable	In a preclinical study, non-small cell lung carcinoma cells overexpressing TP53 P98A demonstrated reduced sensitivity to Roscovotine (seliciclib) induced apoptosis in culture (PMID: 22862161).	22862161
TP53 wild-type	lung non-small cell carcinoma	sensitive	Seliciclib	Preclinical - Cell culture	Actionable	In a preclinical study, Roscovotine (seliciclib) induced substantial apoptosis in non-small cell lung carcinoma cells overexpressing wild-type TP53 in culture (PMID: 22862161).	22862161
TP53 negative	lung non-small cell carcinoma	decreased response	Seliciclib	Preclinical - Cell culture	Actionable	In a preclinical study, TP53-null non-small cell lung carcinoma cells demonstrated reduced sensitivity to Roscovotine (seliciclib) induced apoptosis in culture (PMID: 22862161).	22862161
TP53 Y234C	lung non-small cell carcinoma	decreased response	Seliciclib	Preclinical - Cell culture	Actionable	In a preclinical study, non-small cell lung carcinoma cells overexpressing TP53 Y234C demonstrated reduced sensitivity to Roscovotine (seliciclib) induced apoptosis in culture (PMID: 22862161).	22862161
TP53 S215G	lung non-small cell carcinoma	resistant	Seliciclib	Preclinical - Cell culture	Actionable	In a preclinical study, non-small cell lung carcinoma cells overexpressing TP53 S215G were resistant to Roscovotine (seliciclib) induced apoptosis in culture (PMID: 22862161).	22862161
TP53 Y220C	lung non-small cell carcinoma	resistant	Seliciclib	Preclinical - Cell culture	Actionable	In a preclinical study, non-small cell lung carcinoma cells overexpressing TP53 Y220C were resistant to Roscovotine (seliciclib) induced apoptosis in culture (PMID: 22862161).	22862161
TP53 R175H	lung non-small cell carcinoma	resistant	Seliciclib	Preclinical - Cell culture	Actionable	In a preclinical study, non-small cell lung carcinoma cells overexpressing TP53 R175H were resistant to Roscovotine (seliciclib) induced apoptosis in culture (PMID: 22862161).	22862161