Prevalence of Fragile Histidine Triad Expression in Tumors from Saudi Arabia: A Tissue Microarray Analysis

Bavi, Prashant; Jehan, Zeenath; Atizado, Valerie; Al-Dossari, Hassan; Al‐Dayel, Fouad; Tulbah, Asmah; Amr, Samir S.; Sheikh, Salwa S.; Ezzat, Adnan; El-Solh, Hassan; Uddin, Shahab; Al‐Kuraya, Khawla S.

doi:10.1158/1055-9965.epi-05-0972

Cited by 44 publications

(36 citation statements)

References 66 publications

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“…All samples were analysed in a tissue microarray (TMA) format. TMA construction was performed as described earlier (Kononen et al, 1998;Bavi et al, 2006). Briefly, tissue cylinders with a diameter of 0.6 mm were punched from representative tumor regions of each donor tissue block and brought into recipient paraffin block using a modified semi-automatic robotic precision instrument (Beecher Instruments, Woodland, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

Abubaker¹,

Bavi²,

Al-harbi³

et al. 2008

Oncogene

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Activation of the phosphatidylinositol 3 0 -kinase (PI3K)/ AKT pathway results in an increase in cell proliferation and survival. Somatic mutations within the PI3K catalytic subunit, PIK3CA are common cause of increasing PI3K activity and are believed to be oncogenic in many cancer types. Few reports addressed the association between PIK3CA mutations and tumor progression specifically in microsatellite instable (MSI) colorectal cancer (CRC). In the present study, we have evaluated PIK3CA mutational status in a series of 410 Middle Eastern CRC and 13 colon cell lines to study the prevalence of PIK3CA mutations in MSI cases, PTEN expression in CRC and possibility of therapeutic targeting of this set of patients. PIK3CA mutations were found in four of the cell lines tested and 51 colorectal carcinomas (12.2%). Three of these four mutated cell lines were MSI. PTEN was inactivated in 66.1% of the CRC. Furthermore, we observed a strong association between PIK3CA mutations and MSI status (P ¼ 0.0046) while PTEN loss was more frequent in microsatellite stable (MSS) CRC (P ¼ 0.043). A high prevalence of genetic alterations in PI3K/AKT pathway in Saudi cohort of CRC, predominance of PIK3CA mutations in the MSI subgroup and their possible involvement in development/progression of this subset of CRC are some of the significant findings of our study.

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Section: Methodsmentioning

confidence: 99%

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

Abubaker¹,

Bavi²,

Al-harbi³

et al. 2008

Oncogene

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“…All samples were analyzed in a tissue microarray (TMA) format. TMA construction was performed as described earlier (33,34). The Institutional Review Board of the King Faisal Specialist Hospital and Research Center approved the study.…”

Section: Patient Selection and Tissue Microarray (Tma) Constructionmentioning

confidence: 99%

Dual Targeting of mTOR Activity with Torin2 Potentiates Anticancer Effects of Cisplatin in Epithelial Ovarian Cancer

Hussain

Al-Romaizan

Ahmed

et al. 2015

Mol Med

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Mammalian target of rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K) are two key components of PI3K/Akt/mTOR signaling pathway. Dysregulation of these pathways have been found in many cancers, including epithelial ovarian cancer (EOC), however, the role of mTOR has not been fully elucidated in Middle Eastern EOC. Therefore, we investigated the activation of mTOR complexes (mTORC1 and mTORC2) in a cohort of 156 EOC from Saudi Arabia by immunohistochemistry in a tissue microarray format. mTORC1 and mTORC2 were found to be activated in 55 of 146 (37.7%) and 63 of 140 (45%) of EOC samples, respectively. mTORC1 was significantly associated with mTORC2 (p < 0.0001) activation and both mTOR complexes were significantly associated with p-AKT (p = 0.0205 and 0.0298) and p-P70S6 (p < 0.0001 and 0.0035), respectively. Interestingly, mTOR activation incurred a poor progression-free survival (PFS) (p = 0.0188) in EOC. Next, the in vitro effect of inactivation of mTOR complexes was evaluated using a second-generation mTOR inhibitor, Torin2, on a panel of EOC cell lines. Torin2 treatment decreased cell viability and induced apoptosis in a dose-dependent manner via inactivation of mTORC1 and mTORC2 and their downstream targets in EOC cell lines. Furthermore, treatment of EOC cells with a subtoxic dose of Torin2 potentiated a cisplatin-induced apoptotic response in EOC cell lines. Finally, we studied the in vivo effect of a combination of Torin2 and cisplatin and found that this combination synergistically inhibited tumor growth in nude mice. These studies highlight the importance of targeting the mTOR survival pathway and suggest that cotreatment with cisplatin and Torin2 may be beneficial for the management of EOC.

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“…Tissue microarrays (TMA) were constructed as described previously. 31 The study was approved by the institutional review board of the King Faisal Specialist Hospital and Research Center (Project RAC# 2060008).…”

Section: Patient Samples and Construction Of Tissue Microarraymentioning

confidence: 99%

Overexpression of FoxM1 offers a promising therapeutic target in diffuse large B-cell lymphoma

Uddin¹,

Hussain²,

Ahmed³

et al. 2012

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundFoxM1 has been shown to play a critical role in the pathogenesis of various epithelial malignancies. However, its role in lymphoid malignancies has not been fully clarified. We, therefore, investigated the role of FoxM1 expression in a large cohort of diffuse large B-cell lymphoma samples and panel of cell lines. Design and MethodsFoxM1 expression was investigated in a large series of diffuse large B-cell lymphoma tissues in a tissue microarray format by immunohistochemistry. Apoptosis was measured by flow cytometry and protein expression was detected by immunoblotting using diffuse large B-cell lymphoma cell lines following treatment with either pharmacological inhibitor of FoxM1 or small interference RNA knockdown strategy. Invasion/migration and soft agar colony assays were also performed following treatment with FoxM1 inhibitor. ResultsFoxM1 expression was detected in 84.6% of diffuse large B-cell lymphoma tumors and found to be significantly associated with proliferative tumor marker Ki67 (P<0.0001), matrix metalloproteinases-2 (P=0.0008), matrix metalloproteinases-9 (P=0.0002), S-phase kinase associated protein-2 (P<0.0001) and inversely associated with p27 expression (P=0.0215). Expression of small interference RNA targeted against FoxM1 or treatment of diffuse large B-cell lymphoma cells with thiostrepton caused its downregulation accompanied by decreased expression of matrix metalloproteinases-2 and matrix metalloproteinases-9. Inhibition of FoxM1 in diffuse large B-cell lymphoma cells also decreased invasive and migratory capability, and induced caspase dependent apoptosis via activation of the mitochondrial apoptotic pathway. Finally, combined thiostrepton and bortezomib at sub-toxic doses led to efficient apoptosis in diffuse large B-cell lymphoma cells. ConclusionsAltogether, these results suggest that FoxM1 is over-expressed in the majority of diffuse large Bcell lymphoma samples. These data also indicate that targeting FoxM1 signaling can serve as a potential therapeutic modality in the management of diffuse large B-cell lymphoma.Key words: diffuse large B-cell lymphoma, FoxM1, apoptosis, NHL therapy. B-cell lymphoma. Haematologica 2012;97(7):1092-1100. doi:10.3324/haematol.2011 This is an open-access paper. Citation: Uddin S, Hussain AR, Ahmed M, Siddiqui K, Al-Dayel F, Bavi P, and Al-Kuraya KS. Overexpression of FoxM1 offers a promising therapeutic target in diffuse large Overexpression of FoxM1 offers a promising therapeutic target in diffuse large B-cell lymphoma

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Prevalence of Fragile Histidine Triad Expression in Tumors from Saudi Arabia: A Tissue Microarray Analysis

Cited by 44 publications

References 66 publications

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

Dual Targeting of mTOR Activity with Torin2 Potentiates Anticancer Effects of Cisplatin in Epithelial Ovarian Cancer

Overexpression of FoxM1 offers a promising therapeutic target in diffuse large B-cell lymphoma

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