Homozygous deletions of methylthioadenosine phosphorylase in human biliary tract cancers

Karikari, Collins; Mullendore, Michael E.; Eshleman, James R.; Argani, Pedram; Leoni, Lorenzo M.; Chattopadhyay, Shrikanta; Hidalgo, Manuel; Maitra, Anirban

doi:10.1158/1535-7163.mct-05-0103

Cited by 31 publications

(22 citation statements)

References 15 publications

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“…Although, homozygous deletions of the MTAP gene have been reported in many cancers (Schmid et al, 1998;M'soka et al, 2000;Christopher et al, 2002;García-Castellano et al, 2002;Illei et al, 2003;Hustinx et al, 2005;Karikari et al, 2005;Chow et al, 2006), no previous study has reported MTAP gene deletion and its biological function in human gastric carcinoma. In the present study, we analyzed MTAP deletion and expression in gastric carcinomas and obtained insight into the regulatory and functional roles of MTAP during gastric carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of methylthioadenosin phosphorylase by homozygous deletion in gastric carcinoma

Kim

Min

et al. 2011

Genes Chromosomes & Cancer

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The methylthioadenosine phosphorylase (MTAP) gene is located on 9p21 telomeric to the CDKN2A tumor suppressor gene. Loss of MTAP gene is frequently associated with CDKN2A homozygous deletion. Although the homozygous deletion of MTAP has been reported in various human cancers, its function in gastric carcinogenesis is unknown. Here, we determined the status of the MTAP gene by using a combination of array-based comparative genomic hybridization and oligonucleotide microarray. It was found that MTAP was deleted and downregulated in 2 of 10 gastric cancer cell lines. Of the 494 primary gastric carcinomas examined, MTAP expression at the protein level was reduced in 59 (11.9%). Furthermore, a lack of MTAP expression was found to be associated with poor survival (P = 0.038). The genomic loss of MTAP and CDKN2A in gastric carcinomas was investigated by quantitative real-time PCR. Among 20 gastric carcinomas, two cases showed deletion of both MTAP and CDKN2A, and three samples showed homozygous deletion of MTAP, but not of CDKN2A. An analysis of gastric carcinomas revealed that reduced MTAP expression correlated significantly with a genomic deletion. Furthermore, functional assays by transfecting the siRNA or the expressional cDNA into gastric cancer cell lines demonstrated that MTAP regulates cell growth and invasion. The present study suggests that MTAP plays an important role in the regulation of gastric carcinogenesis and, in particular, that MTAP loss is implicated in some way with tumor growth via the modulation of cellular properties, which, in turn, suggests that MTAP has therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Downregulation of methylthioadenosin phosphorylase by homozygous deletion in gastric carcinoma

Kim

Min

et al. 2011

Genes Chromosomes & Cancer

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“…Cell Viability (MTS) Assay Cell viability was measured using the CellTiter 96 Aqueous Cell Proliferation Assay (Promega, Madison, WI), which relies on the conversion of a tetrazolium compound (MTS) to a colored formazan product by the activity of living cells (28). Briefly, pancreatic cancer cells were plated in 96-well plates and treated with varying concentrations of the XAntags (1396-11, 1396-12, and 1396-34 and the inactive control 1396-28) for 96 h, at which point the assay was terminated, and relative growth inhibition compared with vehicle-treated cells was measured using the CellTiter 96 reagent as described in the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein

Karikari¹,

Roy²,

Tryggestad

et al. 2007

Molecular Cancer Therapeutics

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Resistance to apoptosis is a hallmark of many solid tumors, including pancreatic cancers, and may be the underlying basis for the suboptimal response to chemoradiation therapies. Overexpression of a family of inhibitor of apoptosis proteins (IAP) is commonly observed in pancreatic malignancies. We determined the therapeutic efficacy of recently described small-molecule antagonists of the X-linked IAP (XIAP) in preclinical models of pancreatic cancer. Primary pancreatic cancers were assessed for XIAP expression by immunohistochemistry, using a pancreatic cancer tissue microarray. XIAP small-molecule antagonists (''XAntag''; compounds 1396-11 and 1396-12) and the related compound 1396-28 were tested in vitro in a panel of human pancreatic cancer cell lines (Panc1, Capan1, and BxPC3) and in vivo in s.c. xenograft models for their ability to induce apoptosis and impede neoplastic growth. In addition, pancreatic cancer cell lines were treated with XAntags in conjunction with either tumor necrosis factor -related apoptosis-inducing ligand (TRAIL) or with radiation to determine potential synergy for such dual targeting of the apoptotic machinery. XIAP was overexpressed in 14 of 18 (77%) of primary pancreatic cancers. The XAntags1396-11 and 1396-12, but not the inactive isomer 1396-28, induced profound apoptosis in multiple pancreatic cancer cell lines tested in vitro, with a IC 50 in the range of 2 to 5 Mmol/L. Mechanistic specificity of the XAntags for the baculoviral IAP repeat-2 domain of XIAP was shown by preferential activation of downstream ''effector'' caspases (caspase-3 and caspase-7) versus the upstream ''initiator'' caspase-9. S.c. BxPC3 xenograft growth in athymic mice was significantly inhibited by monotherapy with XAntags; treated xenografts showed marked apoptosis and increased cleavage of caspase-3. Notably, striking synergy was demonstrable when XAntags were combined with either TRAIL or radiation therapy, as measured by growth inhibition in vitro and reduced colony formation in soft agar of pancreatic cancer cell lines, at dosages where these therapeutic modalities had minimal to modest effects when used alone. Finally, XAntags in combination with the standard-of-care agent for advanced pancreatic cancer, gemcitabine, resulted in significantly greater inhibition of in vitro growth than gemcitabine alone. Our results confirm that pharmacologic inhibition of XIAP is a potent therapeutic modality in pancreatic cancers. These antagonists are independently capable of inducing pancreatic cancer cell death and also show synergy when combined with proapoptotic ligands (TRAIL), with radiation, and with a conventional antimetabolite, gemcitabine. These preclinical results suggest that targeting of the apoptotic machinery in pancreatic cancers with XAntags is a promising therapeutic option that warrants further evaluation. [Mol Cancer Ther 2007;6(3):957 -66]

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“…This deletion has been exploited in an attempt to develop targeted chemotherapy regimens mainly focusing on using L-alanosine, an inhibitor of adenylosuccinate dehydrogenase, a component of the de novo purine synthesis pathway. Indeed MTAP-negative cells have been shown to be far more sensitive to L-alanosine than cells replete with the enzyme (6,8,9,11), and this has led to clinical trials evaluating the use of L-alanosine in MTAPdeficient cancers (27). There is an ongoing phase II trial evaluating the activity of pemetrexed in chondrosarcomas which will correlate response with MTAP deletions that have been found in 50% of samples tested thus far (28).…”

Section: Discussionmentioning

confidence: 99%

“…However, these studies compared nonsyngeneic cell lines or evaluated the effect of MTAP overexpression and, until this time, only a weak inhibitor of MTAP was available to assess the role of constitutive enzyme activity (7). Suppression of constitutive MTAP expression by interfering RNA (siRNA) was shown in one report to enhance L-alanosine activity (11). There have been no studies that have addressed the effect of MTAP expression on pemetrexed activity.…”

Section: Introductionmentioning

confidence: 99%

The effect of a novel transition state inhibitor of methylthioadenosine phosphorylase on pemetrexed activity

Chattopadhyay¹,

Zhao²,

Tsai³

et al. 2006

Molecular Cancer Therapeutics

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Pemetrexed is a new-generation antifolate inhibitor of thymidylate synthase (TS) and a weaker inhibitor of glycinamide ribonucleotide transformylase (GARFT) required for de novo purine synthesis. Methylthioadenosine phosphorylase (MTAP) salvages purines by releasing adenine from methylthioadenosine and is often deleted in mesothelioma. The current study addresses the effect of MTAP on pemetrexed activity using a highly potent transition state inhibitor of MTAP, MT-DADMe-Immucillin A (ImmA; K i = 86 pmol/L) in the MTAP(+) NCI-H28 and MTAP(À) NCI-H2052 mesothelioma cell lines. Based on selective nucleoside protection, TS was found to be the primary pemetrexed target in both cell lines with GARFT inhibition requiring 20-to 30-fold higher pemetrexed concentrations. ImmA had no effect on pemetrexed activity but, when thymidine was added, the pemetrexed IC 50 decreased by a factor of f3 in MTAP(+) H28 cells with no effect in MTAP(À) H2052 cells. Conversely, the transfection of MTAP into H2052 cells increased the pemetrexed IC 50 by nearly 3-fold but only in the presence of thymidine; this was reversed by ImmA. An MTAPspecific short interfering RNA produced a 2-fold decrease in pemetrexed IC 50 in MTAP(+) HeLa cells in the presence of thymidine. These data indicate that suppression of constitutive MTAP has no effect on pemetrexed activity when the primary target is TS. There is a modest salutary effect when the pemetrexed target is GARFT alone. [Mol Cancer Ther 2006;5(10):2549 -55]

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Homozygous deletions of methylthioadenosine phosphorylase in human biliary tract cancers

Cited by 31 publications

References 15 publications

Downregulation of methylthioadenosin phosphorylase by homozygous deletion in gastric carcinoma

Downregulation of methylthioadenosin phosphorylase by homozygous deletion in gastric carcinoma

Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein

The effect of a novel transition state inhibitor of methylthioadenosine phosphorylase on pemetrexed activity

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