p21Waf1/Cip1 as a therapeutic target in breast and other cancers

Weiss, Robert H.

doi:10.1016/s1535-6108(03)00308-8

Cited by 235 publications

(260 citation statements)

References 48 publications

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“…p21 has been suggested to have a crucial role in maintaining cell viability upon p53 induction and induction of p21 has been shown to impart cells with a survival advantage [32]. Indeed, we showed that the induction of p21 in response to cucurbitacins was reproducibly higher in HCT116 than in Hke-3 cells (Fig.…”

Section: Induction Of P53 and P21 By Cucurbitacins Is Enhanced In Celmentioning

confidence: 66%

Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis: The role of p53 and p21

Escandell

Kaler

Recio

et al. 2008

Biochemical Pharmacology

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Cucurbitacins have been shown to inhibit proliferation in a variety of cancer cell lines. The aim of this study was to determine their biological activity in colon cancer cell lines that do not harbor activated STAT3, the key target of cucurbitacin. In order to establish the role of activated kRas in the responsiveness of cells to cucurbitacins, we performed experiments in isogenic colon cancer cell lines, HCT116 and Hke-3, which differ only by the presence of an activated kRas allele. We compared the activity of 23, 24-dihydrocucurbitacin B (DHCB) and cucurbitacin R (CCR), two cucurbitacins that we recently isolated, with cucurbitacin I (CCI), a cucurbitacin with established antitumorigenic activity. We showed that cucurbitacins induced dramatic changes in the cytoskeleton (collapse of actin and bundling of tubulin microfilaments), inhibited proliferation and finally induced apoptosis of both HCT116 and Hke3 cells. However, the presence of oncogenic k-Ras significantly decreased the sensitivity of cells to the three cucurbitacins tested, CCR, DHCB and CCI. We confirmed that mutational activation of kRas protects cells from cucurbitacin-induced apoptosis using nontransfromed intestinal epithelial cells with inducible expression of k-RasV12. Cucurbitacins induced the expression of p53 and p21 predominantly in HCT116 cells that harbor mutant Ras. Using HCT116 cells with targeted deletion of p53 or p21 we confirmed that p53 and p21 protect cells from apoptosis induced by cucurbitacins. These results demonstrated that sensitivity of human colon cancer cell lines to cucurbitacins depends on the kRas and p53/p21 status, and established that cucurbitacins can exert antitumorigenic activity in the absence of activated STAT3.

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Section: Induction Of P53 and P21 By Cucurbitacins Is Enhanced In Celmentioning

confidence: 66%

Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis: The role of p53 and p21

Escandell

Kaler

Recio

et al. 2008

Biochemical Pharmacology

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“…Several recent studies have demonstrated that p53-dependent p21 induction inhibits the apoptotic response, and p21 attenuation may make genotoxic chemotherapeutic agents more effective by subverting the normal repair process or, more directly, by promoting the apoptotic process through inhibition of p21 interaction with apoptosis signal-regulating kinase 1, which is upstream of JNK (Asada et al, 1999;Gartel and Tyner, 2002;Weiss, 2003). In our condition, CDDP/triptolide combination attenuated p53 downstream molecules such as p21, MDM2 and Puma which have short half-lives for mRNA and protein, but had no remarkable influence on the expression of Bax, which has relatively longer half-life, and activated JNK evoked mitochondrial apoptosis using Bax transactivation as a proapoptotic mediator.…”

Section: Discussionmentioning

confidence: 99%

Cancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3β with p53

et al. 2008

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To improve conventional chemotherapeutic efficacy, a combination use of traditional medicines is effective but detailed mechanisms have been rarely elucidated. In the this study, we attempted to clarify how triptolide (PG490), an oxygenated diterpene derived from a Chinese herb, enhances the cisplatin (CDDP)-induced cytotoxicity in urothelial cancer cells. Our results showed that a combined CDDP/triptolide therapy induced apoptosis in urothelial cancer cell lines with wild-type p53, but not in those with mutant-type p53 or normal human urothelium. As the mechanism, triptolide suppressed CDDP-induced p53 transcriptional activity, leading to p21 attenuation, which promoted apoptosis via the activation of c-Jun N-terminal kinase (JNK) and Bax. We further demonstrated that the functional regulation of p53 by triptolide was mediated by an intranuclear association of p53 with glycogen synthase kinase-3b (GSK3b), which was inactivated by protein kinase C (PKC). This modulation of the PKC-GSK3b axis by triptolide was observed in a cancer-specific manner. A mouse xenograft model also showed that a combined CDDP/triptolide therapy completely suppressed tumor growth without any side effects. We expect that cancer-specific enhancement of CDDP-induced cytotoxicity with triptolide may effectively overcome the resistance to a CDDP-based conventional chemotherapy as a treatment for urothelial cancer.

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“…A growing body of evidence indicates that control of p21 expression and regulation of its subcellular localization play a central role in cell fate determination in response to several antiproliferative signals. 42 If so, p16 upregulation would initiate cell cycle arrest and apoptosis signals as p53 activation does, and in both cases p21 function would decide the fate of cells. However, we cannot discern whether p21 suppression of p16-induced apoptosis is the result of a direct antiapoptotic function of p21 or whether suppression of apoptosis is dependent on inhibition of CDK2.…”

Section: Discussionmentioning

confidence: 99%

The fate of pancreatic tumor cell lines following p16 overexpression depends on the modulation of CDK2 activity

et al. 2004

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Restitution of lost tumor-suppressor activities may be a promising strategy to target specifically cancer cells. However, the action of ectopically expressed tumor-suppressor genes depends on genetic background of tumoral cells. Ectopic expression of p16 INK4a induces either cell cycle arrest or apoptosis in different pancreatic cancer cell lines. We examined the molecular mechanisms mediating these two different cellular responses to p16 overexpression. Ectopic expression of p16 leads to G1 arrest in NP-9 cells by redistributing p21/p27 CKIs and inhibiting cyclin-dependent kinase CDK2 activity. In contrast, in NP-18 cells cyclin E (CycE)/ CDK2 activity is significantly higher and is not downregulated by p16-mediated redistribution of p21/p27. Moreover, inhibition of CDK4 activity with fascaplysine, which does not affect CycE/ CDK2 activity, reduces pocket protein phosphorylation in both cell lines, but fails to induce growth arrest. Like overexpression of p16, fascaplysine induces apoptosis in NP-18 cells, suggesting that inhibition of D-type cyclin/CDK activity in cells with high levels of CycE/CDK2 activity activates an apoptotic pathway. Inhibition of CycE/CDK2 activity via ectopic expression of p21 in NP-18 cells overexpressing p16 induces growth arrest and prevents p16-mediated apoptosis. Accordingly, silencing of p21 expression by using small interfering RNA switches the fate of p16-expressing NP-9 cells from cell cycle arrest to apoptosis. Our data suggest that, after CDK4/6 inactivation, the fate of pancreatic tumor cells depends on the ability to modulate CDK2 activity.

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p21Waf1/Cip1 as a therapeutic target in breast and other cancers

Cited by 235 publications

References 48 publications

Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis: The role of p53 and p21

Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis: The role of p53 and p21

Cancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3β with p53

The fate of pancreatic tumor cell lines following p16 overexpression depends on the modulation of CDK2 activity

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