Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers

Lin, De; Xu, Lu; Ding, Ling-Wen; Sharma, Arjun; Liu, Li Zhen; Yang, Henry; Tan, Patrick; Vadgama, Jay; Karlan, Beth Y.; Lester, Jenny; Urban, Nicole; Schummer, Michèl; Doan, Ngan; Said, Jonathan; Sun, Hongmao; Walsh, M.A.; Thomas, Craig J.; Patel, Paresma; Yin, Dong; Chan, David; Koeffler, H. Phillip

doi:10.1073/pnas.1218206110

Cited by 62 publications

(85 citation statements)

References 29 publications

(23 reference statements)

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“…6A-C). The involved locus spanned ;2 Mb in length and disrupted genomic structures of several genes including ACTBL2 and a candidate oncogene, PDE4D (Lin et al 2013). …”

Section: Resolving Focal Genomic Amplifications and Rearrangementsmentioning

confidence: 99%

Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability

et al. 2013

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Genomic instability is a hallmark of human cancers, including the 5% caused by human papillomavirus (HPV). Here we report a striking association between HPV integration and adjacent host genomic structural variation in human cancer cell lines and primary tumors. Whole-genome sequencing revealed HPV integrants flanking and bridging extensive host genomic amplifications and rearrangements, including deletions, inversions, and chromosomal translocations. We present a model of ''looping'' by which HPV integrant-mediated DNA replication and recombination may result in viral-host DNA concatemers, frequently disrupting genes involved in oncogenesis and amplifying HPV oncogenes E6 and E7. Our high-resolution results shed new light on a catastrophic process, distinct from chromothripsis and other mutational processes, by which HPV directly promotes genomic instability.

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“…6A-C). The involved locus spanned ;2 Mb in length and disrupted genomic structures of several genes including ACTBL2 and a candidate oncogene, PDE4D (Lin et al 2013). …”

Section: Resolving Focal Genomic Amplifications and Rearrangementsmentioning

confidence: 99%

Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability

et al. 2013

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“…This study showed a connection between PDE4D and AMPK in cancer/cellcycle dynamics (46). Further depletion of PDE4D can cause apoptosis (10%-40%) in multiple types of cancer cells which have elevated expression level of PDE4D (26).…”

Section: Discussionmentioning

confidence: 63%

“…2D). The overexpression of PDE4D has been observed in multiple types of cancer cells originating from the central nervous system (CNS), lung, breast, and melanomas (26). But, so far, there has been no report that the elevated expression of PDE4D is mutation-specific in cancer.…”

Section: Resultsmentioning

confidence: 99%

“…These results indicate that the regulation of PDE4D expression is at the downstream of STK11 and AMPK signaling. Previously, PDE4D has been known as a tumor-promoting factor (26). We investigated whether inhibition of PDE4D would selectively inhibit the growth of cancer cells with aberrant STK11.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, PDE4 has previously been implicated in cancer pathophysiology by altering proliferation and angiogenesis in lung cancer (44). The association of PDE4D expression and cancer progression has been reported in multiple types of cancer (26). Recently, PDE4D7, one of PDE4D isoforms, has been reported as an androgen-independent marker with a role in regulation of prostate cancer cell proliferation (45).…”

Section: Discussionmentioning

confidence: 99%

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Integrated Analysis of Transcriptomes of Cancer Cell Lines and Patient Samples Reveals STK11/LKB1–Driven Regulation of cAMP Phosphodiesterase-4D

Kim

Song

et al. 2014

Molecular Cancer Therapeutics

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The recent proliferation of data on large collections of well-characterized cancer cell lines linked to therapeutic drug responses has made it possible to identify lineage-and mutation-specific transcriptional markers that can help optimize implementation of anticancer agents. Here, we leverage these resources to systematically investigate the presence of mutation-specific transcription markers in a wide variety of cancer lineages and genotypes. Sensitivity and specificity of potential transcriptional biomarkers were simultaneously analyzed in 19 cell lineages grouped into 228 categories based on the mutational genotypes of 12 cancer-related genes. Among a total of 1,455 category-specific expression patterns, the expression of cAMP phosphodiesterase-4D (PDE4D) with 11 isoforms, one of the PDE4(A-D) subfamilies, was predicted to be regulated by a mutant form of serine/threonine kinase 11 (STK11)/liver kinase B1 (LKB1) present in lung cancer. STK11/ LKB1 is the primary upstream kinase of adenine monophosphate-activated protein kinase (AMPK). Subsequently, we found that the knockdown of PDE4D gene expression inhibited proliferation of STK11-mutated lung cancer lines. Furthermore, challenge with a panel of PDE4-specific inhibitors was shown to selectively reduce the growth of STK11-mutated lung cancer lines. Thus, we show that multidimensional analysis of a well-characterized large-scale panel of cancer cell lines provides unprecedented opportunities for the identification of unexpected oncogenic mechanisms and mutation-specific drug targets. Mol Cancer Ther; 13(10); 2463-73. Ó2014 AACR.

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Cyclic AMP‐hydrolyzing phosphodiesterase inhibitors potentiate statin‐induced cancer cell death

et al. 2020

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Dipyridamole, an antiplatelet drug, has been shown to synergize with statins to induce cancer cell-specific apoptosis. However, given the polypharmacology of dipyridamole, the mechanism by which it potentiates statininduced apoptosis remains unclear. Here, we applied a pharmacological approach to identify the activity of dipyridamole specific to its synergistic anticancer interaction with statins. We evaluated compounds that phenocopy the individual activities of dipyridamole and assessed whether they could potentiate statin-induced cell death. Notably, we identified that a phosphodiesterase (PDE) inhibitor, cilostazol, and other compounds that increase intracellular cyclic adenosine monophosphate (cAMP) levels potentiate statin-induced apoptosis in acute myeloid leukemia and multiple myeloma cells. Additionally, we demonstrated that both dipyridamole and cilostazol further inhibit statin-induced activation of sterol regulatory element-binding protein 2, a known modulator of statin sensitivity, in a cAMP-independent manner. Taken together, our data support that PDE inhibitors such as dipyridamole and cilostazol can potentiate statin-induced apoptosis via a dual mechanism. Given that several PDE inhibitors are clinically approved for various indications, they are immediately available for testing in combination with statins for the treatment of hematological malignancies.

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Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers

Cited by 62 publications

References 29 publications

Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability

Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability

Integrated Analysis of Transcriptomes of Cancer Cell Lines and Patient Samples Reveals STK11/LKB1–Driven Regulation of cAMP Phosphodiesterase-4D

Cyclic AMP‐hydrolyzing phosphodiesterase inhibitors potentiate statin‐induced cancer cell death

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