Propranolol Decreases Proliferation of Endothelial Cells Transformed by Kaposi's Sarcoma-Associated Herpesvirus and Induces Lytic Viral Gene Expression

McAllister, Shane C.; Hanson, Ryan S.; Manion, Rory D.

doi:10.1128/jvi.01569-15

Cited by 14 publications

(24 citation statements)

References 30 publications

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“…The racemic propranolol and the S(-) enantiomer increased both KSHV episomes and titers. This agrees with a previous report where propranolol treatment of immortalized KLECs induced to lytic cycle by phorbol esters increased lytic KSHV gene expression and titers, likely by interfering with the cell cycle 24 , rather than having a SOX18-specific effect.…”

Section: Resultssupporting

confidence: 93%

Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production

Gramolelli

Elbasani

Nurminen

et al. 2019

Preprint

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27Kaposi sarcoma (KS) is a tumour of endothelial origin caused by KS herpesvirus (KSHV) infection 28 and suggested to originate from lymphatic endothelial cells (LECs). While KSHV establishes latency 29 in virtually all susceptible cell types, LECs support a spontaneous lytic gene expression program with 30 high viral genome copies and release of infectious virus. Here, we investigated the role of PROX1, 31 SOX18 and COUPTF2, drivers of lymphatic endothelial fate during embryogenesis, in this unique 32 KSHV infection program. We found that these factors were co-expressed in KS tumours with the 33 viral lytic marker K8.1, and that SOX18 and PROX1 regulate KSHV infection via two independent 34 mechanisms. SOX18 binds to the viral origins of replication and its depletion or chemical inhibition 35 significantly reduced the KSHV genome copies in LECs. PROX1 interacts with ORF50, the initiator 36 of the lytic cascade, increases lytic gene expression and virus production and its depletion reduces 37 KSHV spontaneous lytic reactivation. Upon lytic replication, PROX1 binds to the KSHV genome in 38 the promoter region of ORF50 and enhances its transactivation activity. These results demonstrate 39 the importance of two endothelial transcription factors in the regulation of the KSHV life cycle and 40 introduce SOX18 inhibition as a potential, novel therapeutic modality for KS. 41 42 43 KEYWORDS 44 Kaposi sarcoma, KSHV, herpesvirus, K8.1, transcription factors, PROX1, SOX18, lymphatic 45 endothelial cells, viral genome replication, viral reactivation. 46 47 3 MAIN 48Kaposi sarcoma (KS) is an angiogenic endothelial tumour caused by KS herpesvirus (KSHV). KS is 49 the most common cancer among AIDS patients and a frequent malignancy in Sub-Saharan Africa 1 . 50 KS presents with skin lesions that progress from patch to plaque and ultimately to nodular tumours; 51 in advanced disease visceral involvement is also seen 2,3 . The histopathological hallmark of KS is the 52 presence of KSHV-positive spindle cells (SC), the tumour cells of KS 2,3 . The cell of origin of SC has 53 been debated for two decades 3 . The prevailing hypothesis suggests lymphatic endothelial origin, 54 although blood endothelial cells or mesenchymal cells are also candidates 1,4 . In vitro, latency is the 55 default replication program in KSHV-infected cells with undetectable levels of lytic genes expressed. 56 However, KSHV infection of lymphatic, but not blood, endothelial cells (LEC and BEC) leads to a 57 unique infection program characterized by high KSHV genome copies, spontaneous lytic gene 58 expression and release of infectious virus 5-8 . 59 60 During embryonic development, LEC precursors originate from COUPTF2/SOX18 double-positive 61 BECs that physically separate from the cardinal vein to establish a primary lymphatic vascular plexus. 62 In this process, COUPTF2 and SOX18 drive the expression of PROX1 thereby orchestrating LEC 63 differentiation 9,10 . Here, we explored the role of these transcription factors (TF), instrumental for 64 establishment...

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Section: Resultssupporting

confidence: 93%

Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production

Gramolelli

Elbasani

Nurminen

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Strong efficacy of propranolol as a single agent against other vascular tumor types has been reported for infantile hemangioma [ 28 , 29 ], Kaposi's sarcoma [ 30 ], hemangioendothelioma [ 31 - 33 ], and hemangioblastoma [ 34 - 36 ]. Regardless of convention therapy, almost all patients will succumb to cardiac angiosarcoma within a year of diagnosis [ 14 - 18 ], and for patients who cannot or choose not to undergo surgery, chemotherapy, and/ or radiation, supportive care has historically remained their only remaining option.…”

Section: Discussionmentioning

confidence: 99%

Regression of primary cardiac angiosarcoma and metastatic nodules following propranolol as a single agent treatment

2018

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Angiosarcoma is the most common malignant cardiac tumor. Cardiac angiosarcoma is a highly lethal neoplasm that is largely resistant to conventional anti-cancer therapy. Mean survival of patients with cardiac angiosarcoma is only 4 months, and almost all patients will succumb to the disease within 1 year. The beta blocker propranolol is an emerging therapy against angiosarcoma. When combined with conventional therapies, propranolol increases progression free and overall survival in patients with this tumor type. It is currently unknown if propranolol is capable of showing anti-cancer efficacy as a single agent therapy. We report a case of a 61 year old woman diagnosed with primary cardiac angiosarcoma and liver and lung metastases. This patient chose to decline conventional therapy, and instead was prescribed the beta blocker propranolol as a single agent treatment. After 12 months, the mediastinal mass substantially debulked and decreased in size, and the metastatic nodules stabilized or resolved with no evidence of hyper-metabolic activity on PET-CT. This is the first reported data showing long term efficacy of the beta blocker propranolol as a single agent therapy against angiosarcoma.

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“…McAllister et al 26 later found that propranolol decreased the number of KS-associated herpes virus-infected cells by decreasing proliferation. A Spanish case study in 2015 with two HIVnegative KS patients reported significant response with no adverse effect and no recurrence after 20 months using 0.5% topical timolol twice daily for 12 weeks.…”

Section: Kaposi Sarcomamentioning

confidence: 99%

The role of β‐blockers in dermatological treatment: a review

Chen

Tsai

2017

Acad Dermatol Venereol

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Many systemic medications have been used off-label in cutaneous diseases. Use of β-adrenergic-blocking agents has risen in popularity among dermatologists since the discovery of their efficacy in treating infantile haemangioma. There has also been an increase in the interest of the applications of β-blockers in other skin disorders. Overall, β-blockers are effective in treating diseases of vascular origin and promote wound healing. They are relatively safe and inexpensive medications that could be included in the armamentarium against skin diseases.

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Propranolol Decreases Proliferation of Endothelial Cells Transformed by Kaposi's Sarcoma-Associated Herpesvirus and Induces Lytic Viral Gene Expression

Cited by 14 publications

References 30 publications

Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production

Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production

Regression of primary cardiac angiosarcoma and metastatic nodules following propranolol as a single agent treatment

The role of β‐blockers in dermatological treatment: a review

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