Identification of both Myt-1 and Wee-1 as necessary mediators of the p21-independent inactivation of the cdc-2/cyclin B1 complex and growth inhibition of TRAMP cancer cells by genistein

Touny, Lara H. El; Banerjee, Partha P.

doi:10.1002/pros.20495

Cited by 46 publications

(29 citation statements)

References 33 publications

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“…Our observations that low PKMYT1 mRNA expression is common among the most sensitive cell lines to MK-1775 and that knockdown of PKMYT1 can sensitize less responsive cell lines to MK-1775 together suggest functional redundancy between PKMYT1 and WEE1. In support of this, siRNA studies have shown that knockdown of PKMYT1 leads to similar, although less pronounced, abrogation of G 2 cell-cycle arrest and sensitization to DNA-damaging agents (31,36,37). Furthermore, and similar to WEE1, overexpression of PKMYT1 is sufficient to induce a G 2 cell-cycle delay in HeLa cells (38).…”

Section: Discussionmentioning

confidence: 87%

Preclinical Evaluation of the WEE1 Inhibitor MK-1775 as Single-Agent Anticancer Therapy

Guertin

Liu

et al. 2013

Molecular Cancer Therapeutics

152

142

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Inhibition of the DNA damage checkpoint kinase WEE1 potentiates genotoxic chemotherapies by abrogating cell-cycle arrest and proper DNA repair. However, WEE1 is also essential for unperturbed cell division in the absence of extrinsic insult. Here, we investigate the anticancer potential of a WEE1 inhibitor, independent of chemotherapy, and explore a possible cellular context underlying sensitivity to WEE1 inhibition. We show that MK-1775, a potent and selective ATP-competitive inhibitor of WEE1, is cytotoxic across a broad panel of tumor cell lines and induces DNA double-strand breaks. MK-1775-induced DNA damage occurs without added chemotherapy or radiation in S-phase cells and relies on active DNA replication. At tolerated doses, MK-1775 treatment leads to xenograft tumor growth inhibition or regression. To begin addressing potential response markers for MK-1775 monotherapy, we focused on PKMYT1, a kinase functionally related to WEE1. Knockdown of PKMYT1 lowers the EC 50 of MK-1775 by five-fold but has no effect on the cell-based response to other cytotoxic drugs. In addition, knockdown of PKMYT1 increases markers of DNA damage, gH2AX and pCHK1 S345 , induced by MK-1775. In a post hoc analysis of 305 cell lines treated with MK-1775, we found that expression of PKMYT1 was below average in 73% of the 33 most sensitive cell lines. Our findings provide rationale for WEE1 inhibition as a potent anticancer therapy independent of a genotoxic partner and suggest that low PKMYT1 expression could serve as an enrichment biomarker for MK-1775 sensitivity.

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Section: Discussionmentioning

confidence: 87%

Preclinical Evaluation of the WEE1 Inhibitor MK-1775 as Single-Agent Anticancer Therapy

Guertin

Liu

et al. 2013

Molecular Cancer Therapeutics

152

142

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“…Myt1, a member of the wee 1 family of protein kinases, has also been shown to phosphorylate cdc2 at 2 sites (Thr14 and Tyr15) in a cyclindependent manner [45]. Touny and Banerjee [46] have shown that genistein treatment in TRAMP C2 cells increases myt1 expression. Further, the phophorylation of cdc25C is regulated by Polo-like kinase-1 (Plk1) leading to the onset of mitosis [47]; its inhibition culminating in G 2 /M arrest [48].…”

Section: Discussionmentioning

confidence: 99%

Bromelain inhibits nuclear factor kappa‐B translocation, driving human epidermoid carcinoma A431 and melanoma A375 cells through G₂/M arrest to apoptosis

Bhui

Tyagi

Srivastava

et al. 2011

Molecular Carcinogenesis

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Bromelain, obtained from pineapple, is already in use clinically as adjunct in chemotherapy. Our objective was to test its ability to act as a sole anti-cancer agent. Therefore, we describe its anti-proliferative, anti-inflammatory and subsequent anti-cancer effects in vitro, against human epidermoid carcinoma-A431 and melanoma-A375 cells. Bromelain exhibited reduction in proliferation of both these cell-lines and suppressed their potential for anchorage-independent growth. Further, suppression of inflammatory signaling by bromelain was evident by inhibition of Akt regulated-nuclear factor-kappaB activation via suppression of inhibitory-kappaBα phosphorylation and concomitant reduction in cyclooxygenase-2. Since, the inflammatory cascade is well-known to be closely allied to cancer; we studied the effect of bromelain on events/molecules central to it. Bromelain caused depletion of intracellular glutathione and generation of reactive oxygen-species followed by mitochondrial membrane depolarization. This led to bromelain-induced cell-cycle arrest at G(2)/M phase which was mediated by modulation of cyclin B1, phospho-cdc25C, Plk1, phospho-cdc2, and myt1. This was subsequently followed by induction of apoptosis, indicated by membrane-blebbing, modulation of Bax-Bcl-2 ratio, Apaf-1, caspase-9, and caspase-3; chromatin-condensation, increase in caspase-activity and DNA-fragmentation. Bromelain afforded substantial anti-cancer potential in these settings; hence we suggest it as a potential prospect for anti-cancer agent besides only an additive in chemotherapy.

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“…We have found a significant dose-dependent up-regulation of p21 WAF1 expression in genistein treated cancer cells including MDA-MB-231, MDA-MB-435 and MCF-7 breast cancer cells; PC3 and LNCaP prostate cancer cells; H460 and H322 non-small cell lung cancer cells; and HN4 head and neck squamous carcinoma cells [33;34;37-39]. Touny and Banerjee [40] reported the involvement of upstream kinases Myt-1 and Wee-1 in the transcriptional repression of cyclin B1 and the activation of p21 WAF1 in prostate cancer cells. They found genistein treatment increased Myt-1 levels and decreased Wee-1 phosphorylation, providing better insight into the possible mechanism of genistein-induced G2/M arrest.…”

Section: Effects On Cell Cycle Regulationmentioning

confidence: 99%

Multi-targeted therapy of cancer by genistein

Banerjee¹,

Li²,

Wang³

et al. 2008

Cancer Letters

553

383

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Soy isoflavones have been identified as dietary components having an important role in reducing the incidence of breast and prostate cancers in Asian countries. Genistein, the predominant isoflavone found in soy products, has been shown to inhibit the carcinogenesis in animal models. There is a growing body of experimental evidence showing that the inhibition of human cancer cell growth by genisteinis mediated via the modulation of genes that are related to the control of cell cycle and apoptosis. It has been shown that genistein inhibits the activation of NF-κB and Akt signaling pathways, both of which are known to maintain a homeostatic balance between cell survival and apoptosis. Moreover, genistein antagonizes estrogen-and androgen-mediated signaling pathways in the processes of carcinogenesis. Furthermore, genistein has been found to have antioxidant properties, and shown to be a potent inhibitor of angiogenesis and metastasis. Taken together, both in vivo and in vitro studies have clearly shown that genistein, one of the major soy isoflavones, is a promising agent for cancer chemoprevention and further suggest that it could be an adjunct to cancer therapy by virtue of its effects on reversing radioresistance and chemoresistance. In this review, we attempt to provide evidence for these preventive and therapeutic effects of genistein in a succinct manner highlighting comprehensive state-of-the-art knowledge regarding its multi-targeted biological and molecular effects in cancer cells.

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Identification of both Myt-1 and Wee-1 as necessary mediators of the p21-independent inactivation of the cdc-2/cyclin B1 complex and growth inhibition of TRAMP cancer cells by genistein

Abstract: Myt-1 and Wee-1 rather than p21 are necessary for genistein-induced G2/M arrest in TRAMP-C2 cells and their inhibition partially restores proliferation of TRAMP-C2 cells in the presence of genistein.

Cited by 46 publications

References 33 publications

Preclinical Evaluation of the WEE1 Inhibitor MK-1775 as Single-Agent Anticancer Therapy

Preclinical Evaluation of the WEE1 Inhibitor MK-1775 as Single-Agent Anticancer Therapy

Bromelain inhibits nuclear factor kappa‐B translocation, driving human epidermoid carcinoma A431 and melanoma A375 cells through G₂/M arrest to apoptosis

Multi-targeted therapy of cancer by genistein

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Identification of both Myt-1 and Wee-1 as necessary mediators of the p21-independent inactivation of the cdc-2/cyclin B1 complex and growth inhibition of TRAMP cancer cells by genistein

Abstract: Myt-1 and Wee-1 rather than p21 are necessary for genistein-induced G2/M arrest in TRAMP-C2 cells and their inhibition partially restores proliferation of TRAMP-C2 cells in the presence of genistein.

Cited by 46 publications

References 33 publications

Preclinical Evaluation of the WEE1 Inhibitor MK-1775 as Single-Agent Anticancer Therapy

Preclinical Evaluation of the WEE1 Inhibitor MK-1775 as Single-Agent Anticancer Therapy

Bromelain inhibits nuclear factor kappa‐B translocation, driving human epidermoid carcinoma A431 and melanoma A375 cells through G2/M arrest to apoptosis

Multi-targeted therapy of cancer by genistein

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Product

Resources

About

Bromelain inhibits nuclear factor kappa‐B translocation, driving human epidermoid carcinoma A431 and melanoma A375 cells through G₂/M arrest to apoptosis