mTOR Inhibitors Block Kaposi Sarcoma Growth by Inhibiting Essential Autocrine Growth Factors and Tumor Angiogenesis

Roy, Debasmita; Sin, Sang-Hoon; Lucas, Amy; Venkataramanan, Raman; Wang, Ling; Eason, Anthony; Chavakula, Veenadhari; Hilton, Isaac B.; Tamburro, Kristen M.; Damania, Blossom; Dittmer, Dirk P.

doi:10.1158/0008-5472.can-12-1851

Cited by 64 publications

(64 citation statements)

References 58 publications

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“…One difference between cyclosporine A and sirolimus is that cyclophillin, the target of cyclosporine is only expressed in T cells, whereas mTOR, the target of rapamycin is expressed in T cells, B cells, endothelial cells, and in most KS tumors. Even established KS lesions respond to rapamycin directly and independently of immune reconstitution in AIDS KS [74] and immunodeficient preclinical models [103], though rapamycin primarily stalls tumor growth leading to stable disease rather than inducing tumor regression outright.…”

Section: Update On Treatment Approachesmentioning

confidence: 99%

Diagnosis and Treatment of Kaposi Sarcoma

2017

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Kaposi Sarcoma (KS) is the most common neoplasm of people living with HIV today. In Sub-Saharan Africa KS is among the most common cancers in men, overall. Not only HIV+ individuals present with KS; any immune compromised person infected with Kaposi Sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 is at risk: the elderly, children in KSHV-endemic areas, and transplant recipients. KS diagnosis is based on detection of the viral protein LANA in the biopsy, but not all cases of KS are the same or will respond to the same therapy. Standard KS therapy has not changed in 20 years, but newer modalities are on the horizon and will be discussed.

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Section: Update On Treatment Approachesmentioning

confidence: 99%

Diagnosis and Treatment of Kaposi Sarcoma

2017

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“…Switching from cyclosporine A to rapamycin as the primary immunosuppressant has become the first line of therapy for transplant KS. The clinical phenotype can be recapitulated in preclinical models of KS and PEL (175)(176)(177)(178)(179). In KS, targeting mTOR was associated with a decrease in VEGF production.…”

Section: Viral Mirnas Support Viral Infection and Latent Persistencementioning

confidence: 99%

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Dittmer

Damania

2016

Journal of Clinical Investigation

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175

152

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“…While the mammalian target of the rapamycin complex 1 (mTORC1) has been shown to directly phosphorylate Ser-351, inhibitors of mTORC1 only partially decrease SQSTM1 phosphorylation in human hepatocellular carcinoma cells, suggesting that other kinases are also involved in Ser-351 phosphorylation (9). Interestingly, several KSHV proteins have been shown to activate the mTOR pathway, and mTOR inhibitors were proposed to have antitumor activity against Kaposi's sarcoma (85,86). Future studies are required to determine the role of mTOR in Nrf2 activation and to examine the mechanism of SQSTM1 accumulation and phosphorylation in KSHV-infected cells.…”

Section: Fig 11mentioning

confidence: 99%

Kaposi's Sarcoma-Associated Herpesvirus Induces Nrf2 Activation in Latently Infected Endothelial Cells through SQSTM1 Phosphorylation and Interaction with Polyubiquitinated Keap1

Gjyshi

Flaherty

Veettil

et al. 2015

J Virol

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Nuclear factor erythroid 2-related factor 2 (Nrf2), the cellular master regulator of the antioxidant response, dissociates from its inhibitor Keap1 when activated by stress signals and participates in the pathogenesis of viral infections and tumorigenesis. Early during de novo infection of endothelial cells, KSHV induces Nrf2 through an intricate mechanism involving reactive oxygen species (ROS) and prostaglandin E2 (PGE2). When we investigated the Nrf2 activity during latent KSHV infection, we observed increased nuclear serine-40-phosphorylated Nrf2 in human KS lesions compared to that in healthy tissues. Using KSHV long-term-infected endothelial cells (LTC) as a cellular model for KS, we demonstrated that KSHV infection induces Nrf2 constitutively by extending its half-life, increasing its phosphorylation by protein kinase C (PKC) via the infection-induced cyclooxygenase-2 (COX-2)/PGE2 axis and inducing its nuclear localization. Nrf2 knockdown in LTC decreased expression of antioxidant genes and genes involved in KS pathogenesis such as the NAD(P)H quinone oxidase 1 (NQO1), gamma glutamylcysteine synthase heavy unit (␥GCSH), the cysteine transporter (xCT), interleukin 6 (IL-6), and vascular endothelial growth factor A (VEGF-A) genes. Nrf2 activation was independent of oxidative stress but dependent on the autophagic protein sequestosome-1 (SQSTM1; p62). SQSTM1 levels were elevated in LTC, a consequence of protein accumulation due to decreased autophagy and Nrf2-mediated transcriptional activation. SQSTM1 was phosphorylated on serine-351 and -403, while Keap1 was polyubiquitinated with lysine-63-ubiquitin chains, modifications known to increase their mutual affinity and interaction, leading to Keap1 degradation and Nrf2 activation. The latent KSHV protein Fas-associated death domain-like interleukin-1␤-converting enzyme-inhibitory protein (vFLIP) increased SQSTM1 expression and activated Nrf2. Collectively, these results demonstrate that KSHV induces SQSTM1 to constitutively activate Nrf2, which is involved in the regulation of genes participating in KSHV oncogenesis. IMPORTANCEThe transcription factor Nrf2 is activated by stress signals, including viral infection, and responds by activating the transcription of cytoprotective genes. Recently, Nrf2 has been implicated in oncogenesis and was shown to be activated during de novo KSHV infection of endothelial cells through ROS-dependent pathways. The present study was undertaken to determine the mechanism of Nrf2 activation during prolonged latent infection of endothelial cells, using an endothelial cell line latently infected with KSHV. We show that Nrf2 activation was elevated in KSHV latently infected endothelial cells independently of oxidative stress but dependent on the autophagic protein sequestosome-1 (SQSTM1), which was involved in the degradation of the Nrf2 inhibitor Keap1. Furthermore, our results indicated that the KSHV latent protein vFLIP participates in Nrf2 activation. This study suggests that KSHV hijacks the host's autophagic protein SQS...

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mTOR Inhibitors Block Kaposi Sarcoma Growth by Inhibiting Essential Autocrine Growth Factors and Tumor Angiogenesis

Cited by 64 publications

References 58 publications

Diagnosis and Treatment of Kaposi Sarcoma

Diagnosis and Treatment of Kaposi Sarcoma

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Kaposi's Sarcoma-Associated Herpesvirus Induces Nrf2 Activation in Latently Infected Endothelial Cells through SQSTM1 Phosphorylation and Interaction with Polyubiquitinated Keap1

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