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Article: PLK1 and PARP positively correlate in Middle Eastern breast cancer and their combined inhibition overcomes PARP inhibitor resistance in triple negative breast cancer.

Siraj, Abdul K / Poyil, Pratheesh Kumar / Padmaja, Divya / Parvathareddy, Sandeep Kumar / Alobaisi, Khadija / Thangavel, Saravanan / Diaz, Roxanne / Begum, Rafia / Almalik, Osama / Al-Dayel, Fouad / Al-Kuraya, Khawla S

Frontiers in oncology

2024 Volume 13, Page(s) 1286585

Abstract: Background: Despite advancements in treatment approaches, patients diagnosed with aggressive breast cancer (BC) subtypes typically face an unfavorable prognosis. Globally, these cancers continue to pose a significant threat to women's health, leading to ...

Abstract	Background: Despite advancements in treatment approaches, patients diagnosed with aggressive breast cancer (BC) subtypes typically face an unfavorable prognosis. Globally, these cancers continue to pose a significant threat to women's health, leading to substantial morbidity and mortality. Consequently, there has been a significant struggle to identify viable molecular targets for therapeutic intervention in these patients. Polo-like Kinase-1 (PLK1) represents one of these molecular targets currently undergoing rigorous scrutiny for the treatment of such tumors. Yet, its role in the pathogenesis of BC in Middle Eastern ethnicity remains unexplored. Methods: We investigated the expression of PLK1 protein in a cohort of more than 1500 Middle Eastern ethnicity BC cases by immunohistochemistry. Association with clinicopathological parameters and prognosis were performed. Results: Overexpression of PLK1 was detected in 27.4% of all BC cases, and this was notably correlated with aggressive clinicopathological markers. PLK1 was enriched in the triple-negative breast cancer (TNBC) subtype and exhibited poor overall survival (p = 0.0347). Notably, there was a positive correlation between PLK1 and PARP overexpression, with co-expression of PLK1 and PARP observed in 15.7% of cases and was associated with significantly poorer overall survival (OS) compared to the overexpression of either protein alone (p = 0.0050). Conclusion: Our results shed light on the role of PLK1 in the pathogenesis and prognosis of Middle Eastern BC and support the potential clinical development of combined inhibition of PLK1 and PARP, a strategy that could potentially broaden the use of PLK1 and PARP inhibitors beyond BC cases lacking
Language	English
Publishing date	2024-01-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1286585
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Article ; Online: PLK1 and FoxM1 expressions positively correlate in papillary thyroid carcinoma and their combined inhibition results in synergistic anti-tumor effects.

Poyil, Pratheesh Kumar / Siraj, Abdul K / Padmaja, Divya / Parvathareddy, Sandeep Kumar / Thangavel, Saravanan / Alobaisi, Khadija / Diaz, Roxanne / Begum, Rafia / Haqawi, Wael / Al-Sobhi, Saif S / Al-Dayel, Fouad / Al-Kuraya, Khawla S

Molecular oncology

2024 Volume 18, Issue 3, Page(s) 691–706

Abstract: Polo-like kinase 1 (PLK1; also known as serine/threonine-protein kinase PLK1) serves as a central player in cell proliferation, exerting critical regulatory roles in mitotic processes and cell survival. We conducted an analysis of PLK1 protein expression ...

Abstract	Polo-like kinase 1 (PLK1; also known as serine/threonine-protein kinase PLK1) serves as a central player in cell proliferation, exerting critical regulatory roles in mitotic processes and cell survival. We conducted an analysis of PLK1 protein expression in a large cohort of samples from papillary thyroid carcinoma (PTC) patients and examined its functional significance in PTC cell lines, both in vitro and in vivo. PLK1 overexpression was noted in 54.2% of all PTC and was significantly associated with aggressive clinicopathological parameters; it was also found to be an independent prognostic marker for shorter recurrence-free survival. Given the significant association between PLK1 and forkhead box protein M1 (FoxM1), and their concomitant overexpression in a large proportion of PTC samples, we explored their correlation and their combined inhibitions in PTC in vitro and in vivo. Inhibition of PLK1 expression indeed suppressed cell proliferation, leading to cell cycle arrest and apoptosis in PTC cell lines. Significantly, the downregulation of PLK1 reduced the self-renewal capability of spheroids formed from PTC cells. Immunoprecipitation analysis shows that PLK1 binds to FoxM1 and vice versa in vitro. Mechanistically, PLK1 knockdown suppresses FoxM1 expression, whereas inhibition of FoxM1 does not affect PLK1 expression, which suggests that PLK1 acts through the FoxM1 pathway. The combined treatment of a PLK1 inhibitor (volasertib) and a FoxM1 inhibitor (thiostrepton) demonstrated a synergistic effect in reducing PTC cell growth in vitro and delaying tumor growth in vivo. This study highlights the important role of PLK1 in PTC tumorigenesis and prognosis. It also highlights the synergistic therapeutic potential of dual-targeting PLK1 and FoxM1 in PTC, unveiling a potential innovative therapeutic strategy for managing aggressive forms of PTC.
MeSH term(s)	Humans ; Apoptosis ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Forkhead Box Protein M1/genetics ; Forkhead Box Protein M1/metabolism ; Gene Expression Regulation, Neoplastic ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Thyroid Cancer, Papillary/genetics ; Thyroid Neoplasms/metabolism
Chemical Substances	Cell Cycle Proteins ; Forkhead Box Protein M1 ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Proto-Oncogene Proteins ; PLK1 protein, human ; FOXM1 protein, human
Language	English
Publishing date	2024-02-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2415106-3
ISSN	1878-0261 ; 1574-7891
ISSN (online)	1878-0261
ISSN	1574-7891
DOI	10.1002/1878-0261.13610
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Article ; Online: Lynch Syndrome Identification in Saudi Cohort of Endometrial Cancer Patients Screened by Universal Approach.

Bu, Rong / Siraj, Abdul K / Parvathareddy, Sandeep Kumar / Iqbal, Kaleem / Azam, Saud / Qadri, Zeeshan / Al-Rasheed, Maha / Haqawi, Wael / Diaz, Mark / Alobaisi, Khadija / Annaiyappanaidu, Padmanaban / Siraj, Nabil / AlHusaini, Hamed / Alomar, Osama / Al-Badawi, Ismail A / Al-Dayel, Fouad / Al-Kuraya, Khawla S

International journal of molecular sciences

2022 Volume 23, Issue 20

Abstract: Lynch syndrome (LS) is the most common cause of inherited endometrial cancer (EC). The prevalence and molecular characteristic of LS in Middle Eastern women with EC have been underexplored. To evaluate the frequency of LS in a cohort of EC patients from ... ...

Abstract	Lynch syndrome (LS) is the most common cause of inherited endometrial cancer (EC). The prevalence and molecular characteristic of LS in Middle Eastern women with EC have been underexplored. To evaluate the frequency of LS in a cohort of EC patients from Saudi Arabia, a total of 436 EC cases were screened utilizing immunohistochemistry (IHC),
MeSH term(s)	Humans ; Female ; Colorectal Neoplasms, Hereditary Nonpolyposis/epidemiology ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis/pathology ; MutS Homolog 2 Protein/genetics ; DNA Mismatch Repair/genetics ; Saudi Arabia/epidemiology ; Germ-Line Mutation/genetics ; DNA Methylation ; Endometrial Neoplasms/epidemiology ; Endometrial Neoplasms/genetics ; Endometrial Neoplasms/pathology ; Microsatellite Instability
Chemical Substances	MutS Homolog 2 Protein (EC 3.6.1.3)
Language	English
Publishing date	2022-10-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms232012299
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Article ; Online: CHD4 Predicts Aggressiveness in PTC Patients and Promotes Cancer Stemness and EMT in PTC Cells.

Pratheeshkumar, Poyil / Siraj, Abdul K / Divya, Sasidharan Padmaja / Parvathareddy, Sandeep Kumar / Alobaisi, Khadija / Al-Sobhi, Saif S / Al-Dayel, Fouad / Al-Kuraya, Khawla S

International journal of molecular sciences

2021 Volume 22, Issue 2

Abstract: Chromodomain-helicase-DNA-binding protein 4 (CHD4), a core subunit of the nucleosome remodeling and deacetylation (NuRD) complex is highly expressed in several cancers. However, its role in the pathogenesis and progression of papillary thyroid carcinoma ( ...

Abstract	Chromodomain-helicase-DNA-binding protein 4 (CHD4), a core subunit of the nucleosome remodeling and deacetylation (NuRD) complex is highly expressed in several cancers. However, its role in the pathogenesis and progression of papillary thyroid carcinoma (PTC) has not been investigated. We investigated the prognostic significance of CHD4 in a large cohort of Middle Eastern PTC patients and explored the functional role of CHD4 in regulating cancer stemness and EMT in PTC cells. CHD4 overexpression was observed in 45.3% (650/1436) of PTCs, and was associated with aggressive clinico-pathological parameters and worse outcome. Functional analysis using PTC cell lines showed that forced expression of CHD4 promoted cell proliferation, spheroid growth, migration, invasion and progression of epithelial to mesenchymal transition (EMT) in PTC cells whereas its knockdown reversed the effect. Methylation of E-cadherin was associated with loss of expression in CHD4 expressing cells, while CHD4 depletion reactivated E-cadherin expression. Most importantly, knockdown of mesenchymal transcriptional factors, Snail1 or Zeb1, attenuated the spheroid growth in CHD4 expressing PTC cells, showing a potential link between EMT activation and stemness maintenance in PTC. These findings suggest that CHD4 might be a promising therapeutic target in the treatment of patients with an aggressive subtype of PTC.
MeSH term(s)	Adult ; Cadherins/genetics ; Cadherins/metabolism ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Proliferation/genetics ; Cohort Studies ; Epithelial-Mesenchymal Transition/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Kaplan-Meier Estimate ; Male ; Mi-2 Nucleosome Remodeling and Deacetylase Complex/genetics ; Mi-2 Nucleosome Remodeling and Deacetylase Complex/metabolism ; Middle Aged ; Neoplastic Stem Cells/metabolism ; Prognosis ; Thyroid Cancer, Papillary/genetics ; Thyroid Cancer, Papillary/metabolism ; Thyroid Cancer, Papillary/pathology ; Thyroid Neoplasms/genetics ; Thyroid Neoplasms/metabolism ; Thyroid Neoplasms/pathology
Chemical Substances	CHD4 protein, human ; Cadherins ; Mi-2 Nucleosome Remodeling and Deacetylase Complex (EC 3.5.1.98)
Language	English
Publishing date	2021-01-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22020504
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Article ; Online: Loss of ZNF677 Expression Is an Independent Predictor for Distant Metastasis in Middle Eastern Papillary Thyroid Carcinoma Patients.

Siraj, Abdul K / Poyil, Pratheesh Kumar / Parvathareddy, Sandeep Kumar / Alobaisi, Khadija / Ahmed, Saeeda O / Al-Sobhi, Saif S / Al-Dayel, Fouad / Al-Kuraya, Khawla S

International journal of molecular sciences

2021 Volume 22, Issue 15

Abstract: Thyroid cancer incidence has increased in recent decades. Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Approximately 30% of PTC patients develop recurrence or distant metastasis and tend to have poor prognosis. Therefore, ... ...

Abstract	Thyroid cancer incidence has increased in recent decades. Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Approximately 30% of PTC patients develop recurrence or distant metastasis and tend to have poor prognosis. Therefore, the identification of targetable biomarkers in this subset of patients is of great importance. Accumulating evidence indicates that zinc finger protein 677 (ZNF677), which belongs to the zinc finger protein family, is an important effector during the progression of multiple malignancies. However, its role in Middle Eastern PTC patients has not been fully illustrated. Here, we uncovered the molecular mechanism and the clinical impact of ZNF677 expression in a large cohort of more than 1200 Middle Eastern PTC and 15 metastatic tissues. We demonstrated that ZNF677 is frequently downregulated in primary PTC (13.6%, 168/1235) and showed that complete loss of expression of ZNF677 is significantly associated with aggressive clinico-pathological markers such as extrathyroidal extension (
MeSH term(s)	Adult ; Apoptosis ; Biomarkers, Tumor/metabolism ; Case-Control Studies ; Cell Movement ; Cell Proliferation ; Cohort Studies ; DNA-Binding Proteins/metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Middle Aged ; Middle East/epidemiology ; Prognosis ; Survival Rate ; Thyroid Cancer, Papillary/epidemiology ; Thyroid Cancer, Papillary/metabolism ; Thyroid Cancer, Papillary/secondary ; Thyroid Neoplasms/epidemiology ; Thyroid Neoplasms/metabolism ; Thyroid Neoplasms/pathology ; Tumor Cells, Cultured
Chemical Substances	Biomarkers, Tumor ; DNA-Binding Proteins ; ZNF677 protein, human
Language	English
Publishing date	2021-07-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22157833
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Article: Krupple-Like Factor 5 is a Potential Therapeutic Target and Prognostic Marker in Epithelial Ovarian Cancer.

Siraj, Abdul K / Pratheeshkumar, Poyil / Divya, Sasidharan Padmaja / Parvathareddy, Sandeep Kumar / Alobaisi, Khadija A / Thangavel, Saravanan / Siraj, Sarah / Al-Badawi, Ismail A / Al-Dayel, Fouad / Al-Kuraya, Khawla S

Frontiers in pharmacology

2020 Volume 11, Page(s) 598880

Abstract: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. Despite current therapeutic and surgical options, advanced EOC shows poor prognosis. Identifying novel molecular therapeutic targets is highly needed in the management of EOC. ... ...

Abstract	Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. Despite current therapeutic and surgical options, advanced EOC shows poor prognosis. Identifying novel molecular therapeutic targets is highly needed in the management of EOC. Krupple-like factor 5 (KLF5), a zinc-finger transcriptional factor, is highly expressed in a variety of cancer types. However, its role and expression in EOC is not fully illustrated. Immunohistochemical analysis was performed to assess KLF5 protein expression in 425 primary EOC samples using tissue microarray. We also addressed the function of KLF5 in EOC and its interaction with signal transducer and activator of transcription 3 (STAT3) signaling pathway. We found that KLF5 overexpressed in 53% (229/425) of EOC samples, and is associated with aggressive markers. Forced expression of KLF5 enhanced cell growth in low expressing EOC cell line, MDAH2774. Conversely, knockdown of KLF5 reduced cell growth, migration, invasion and progression of epithelial to mesenchymal transition in KLF5 expressing cell lines, OVISE and OVSAHO. Importantly, silencing of KLF5 decreased the self-renewal ability of spheroids generated from OVISE and OVSAHO cell lines. In addition, downregulation of KLF5 potentiated the effect of cisplatin to induce apoptosis in these cell lines. These data reveals the pro-tumorigenic role of KLF5 in EOC and uncover its role in activation of STAT3 signaling pathway, suggesting the importance of KLF5 as a potential therapeutic target for EOC therapy.
Language	English
Publishing date	2020-12-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2020.598880
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Article ; Online: A very low incidence of BRAF mutations in Middle Eastern colorectal carcinoma.

Siraj, Abdul K / Bu, Rong / Prabhakaran, Sarita / Bavi, Prashant / Beg, Shaham / Al Hazmi, Mohsen / Al-Rasheed, Maha / Alobaisi, Khadija / Al-Dayel, Fouad / AlManea, Hadeel / Al-Sanea, Nasser / Uddin, Shahab / Al-Kuraya, Khawla S

Molecular cancer

2014 Volume 13, Page(s) 168

Abstract: Background: Recent studies emphasize the role of BRAF as a genetic marker for prediction, prognosis and risk stratification in colorectal cancer. Earlier studies have reported the incidence of BRAF mutations in the range of 5-20% in colorectal ... ...

Abstract	Background: Recent studies emphasize the role of BRAF as a genetic marker for prediction, prognosis and risk stratification in colorectal cancer. Earlier studies have reported the incidence of BRAF mutations in the range of 5-20% in colorectal carcinomas (CRC) and are predominantly seen in the serrated adenoma-carcinoma pathway characterized by microsatellite instability (MSI-H) and hypermethylation of the MLH1 gene in the setting of the CpG island methylator phenotype (CIMP). Due to the lack of data on the true incidence of BRAF mutations in Saudi Arabia, we sought to analyze the incidence of BRAF mutations in this ethnic group. Methods: 770 CRC cases were analyzed for BRAF and KRAS mutations by direct DNA sequencing. Results: BRAF gene mutations were seen in 2.5% (19/757) CRC analyzed and BRAF V600E somatic mutation constituted 90% (17/19) of all BRAF mutations. BRAF mutations were significantly associated with right sided tumors (p = 0.0019), MSI-H status (p = 0.0144), CIMP (p = 0.0017) and a high proliferative index of Ki67 expression (p = 0.0162). Incidence of KRAS mutations was 28.6% (216/755) and a mutual exclusivity was noted with BRAF mutations (p = 0.0518; a trend was seen). Conclusion: Our results highlight the low incidence of BRAF mutations and CIMP in CRC from Saudi Arabia. This could be attributed to ethnic differences and warrant further investigation to elucidate the effect of other environmental and genetic factors. These findings indirectly suggest the possibility of a higher incidence of familial hereditary colorectal cancers especially Hereditary non polyposis colorectal cancer (HNPCC) syndrome /Lynch Syndrome (LS) in Saudi Arabia.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Adenomatous Polyposis Coli/genetics ; Adenomatous Polyposis Coli/pathology ; Aged ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/pathology ; CpG Islands ; DNA Methylation/genetics ; Female ; Humans ; Male ; Microsatellite Instability ; Middle Aged ; MutL Protein Homolog 1 ; Mutation ; Nuclear Proteins ; Proto-Oncogene Proteins B-raf/genetics ; Saudi Arabia
Chemical Substances	Adaptor Proteins, Signal Transducing ; MLH1 protein, human ; Nuclear Proteins ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; MutL Protein Homolog 1 (EC 3.6.1.3)
Language	English
Publishing date	2014-07-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1476-4598
ISSN (online)	1476-4598
DOI	10.1186/1476-4598-13-168
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Article: PLK1 and PARP positively correlate in Middle Eastern breast cancer and their combined inhibition overcomes PARP inhibitor resistance in triple negative breast cancer.

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Article ; Online: PLK1 and FoxM1 expressions positively correlate in papillary thyroid carcinoma and their combined inhibition results in synergistic anti-tumor effects.

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In stock of ZB MED Cologne/Königswinter

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Article ; Online: Lynch Syndrome Identification in Saudi Cohort of Endometrial Cancer Patients Screened by Universal Approach.

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Article ; Online: CHD4 Predicts Aggressiveness in PTC Patients and Promotes Cancer Stemness and EMT in PTC Cells.

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Article ; Online: Loss of ZNF677 Expression Is an Independent Predictor for Distant Metastasis in Middle Eastern Papillary Thyroid Carcinoma Patients.

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Article: Krupple-Like Factor 5 is a Potential Therapeutic Target and Prognostic Marker in Epithelial Ovarian Cancer.

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Article ; Online: A very low incidence of BRAF mutations in Middle Eastern colorectal carcinoma.

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