Doxorubicin inhibits PD-L1 expression by enhancing TTP-mediated decay of PD-L1 mRNA in cancer cells

Kim, Dong Jun; Jang, Ji Hun; Ham, Soo Youn; Choi, Seong Hee; Park, Sung Soon; Jeong, Sang Hoon; Kim, Beom Chang; Jeon, Do Yong; Lee, Byung Ju; Ko, Byung Kyun; Park, Jeong Woo; Cho, Wha Ja

doi:10.1016/j.bbrc.2019.11.106

Cited by 22 publications

(17 citation statements)

References 23 publications

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“…The 3′UTR plays an important role in the RBP‐mediated post‐transcriptional regulation of genes 37‐39 . We confirmed that TARBP2 could suppress luciferase activity through the 3′UTRs of antiangiogenic genes and reduced their mRNA stability.…”

Section: Discussionsupporting

confidence: 65%

“…In this study, we identified the previously undiscovered role of TARBP2 in the regulation of tumor angiogenesis, which was The 3′UTR plays an important role in the RBP-mediated posttranscriptional regulation of genes. [37][38][39] We confirmed that TARBP2 could suppress luciferase activity through the 3′UTRs of antiangiogenic genes and reduced their mRNA stability. It has been reported that the dsRBD1 and dsRBD2 domains are essential for TARBP2mediated double-stranded RNA substrate recognition, binding, and processing.…”

Section: Discussionsupporting

confidence: 61%

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TARBP2 promotes tumor angiogenesis and metastasis by destabilizing antiangiogenic factor mRNAs

Zhou

et al. 2021

Cancer Science

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Tumor angiogenesis is a crucial step in the further growth and metastasis of solid tumors. However, its regulatory mechanism remains unclear. Here, we showed that TARBP2, an RNA‐binding protein, played a role in promoting tumor‐induced angiogenesis both in vitro and in vivo through degrading the mRNAs of antiangiogenic factors, including thrombospondin1/2 (THBS1/2), tissue inhibitor of metalloproteinases 1 (TIMP1), and serpin family F member 1 (SERPINF1), by targeting their 3′untranslated regions (3′UTRs). Overexpression of TARBP2 promotes tumor cell–induced angiogenesis, while its knockdown inhibits tumor angiogenesis. Clinical cohort analysis revealed that high expression level of TARBP2 was associated with poor survival of lung cancer and breast cancer patients. Mechanistically, TARBP2 physically interacts with the stem‐loop structure located in the 3′UTR of antiangiogenic transcripts, leading to mRNA destabilization by the dsRNA‐binding domains 1/2 (dsRBDs1/2). Notably, the expression level of TARBP2 in human tumor tissue is negatively correlated with the expression of antiangiogenic factors, including THBS1/2, and brain‐specific angiogenesis inhibitor 1 (BAI1). Moreover, TARBP2 expression is strongly associated with tumor angiogenesis in a group of human lung cancer samples. Collectively, our results highlight that TARBP2 is a novel tumor angiogenesis regulator that could promote tumor angiogenesis by selectively downregulating antiangiogenic gene expression.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionsupporting

confidence: 61%

TARBP2 promotes tumor angiogenesis and metastasis by destabilizing antiangiogenic factor mRNAs

Zhou

et al. 2021

Cancer Science

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“…In this type of cancer, immune escape is mediated by phosphorylating ERK or by increasing the stability of PD-L1 mRNA (95). The phosphorylation of TTP downstream of ERK causes stabilization of PD-L1 mRNA (93). The relevance of TTP and PD-L1 in the anti-tumor immune response is supported by current evidence (91)(92)(93)(94), which demonstrates that TTP could be a novel biomarker in cancer immunotherapy (Figure 5).…”

Section: Ttp Plays An Important Role In Immune Surveillance In the Tmementioning

confidence: 82%

“…Doxorubicin can reduce PD-L1 expression in cancer cells (93). The underlying molecular mechanism involves anti-tumor immunity, which is achieved by increasing TTP expression and subsequently downregulating PD-L1 expression.…”

Section: Ttp Plays An Important Role In Immune Surveillance In the Tmementioning

confidence: 99%

Tristetraprolin, a Potential Safeguard Against Carcinoma: Role in the Tumor Microenvironment

et al. 2021

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Tristetraprolin (TTP), a well-known RNA-binding protein, primarily affects the expression of inflammation-related proteins by binding to the targeted AU-rich element in the 3’ untranslated region after transcription and subsequently mediates messenger RNA decay. Recent studies have focused on the role of TTP in tumors and their related microenvironments, most of which have referred to TTP as a potential tumor suppressor involved in regulating cell proliferation, apoptosis, and metastasis of various cancers, as well as tumor immunity, inflammation, and metabolism of the microenvironment. Elevated TTP expression levels could aid the diagnosis and treatment of different cancers, improving the prognosis of patients. The aim of this review is to describe the role of TTP as a potential safeguard against carcinoma.

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“…Another limitation of this therapy is related to the immunosuppressive effects induced by PLP-induced expression of PD-1, a negative regulator of T cell activation [47]. However, recently published data have indicated that DOX inhibited the expression of PD-L1 on cancer cells [48,49].…”

Section: Discussionmentioning

confidence: 99%

Overcoming Intrinsic Doxorubicin Resistance in Melanoma by Anti-Angiogenic and Anti-Metastatic Effects of Liposomal Prednisolone Phosphate on Tumor Microenvironment

Licărete

Rauca

Lupuţ

et al. 2020

IJMS

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Regardless of recent progress, melanoma is very difficult to treat, mainly due to the drug resistance modulated by tumor cells as well as by the tumor microenvironment (TME). Among the immune cells recruited at the tumor site, tumor associated macrophages (TAMs) are the most abundant, promoting important tumorigenic processes: angiogenesis, inflammation and invasiveness. Furthermore, it has been shown that TAMs are involved in mediating the drug resistance of melanoma cells. Thus, in the present study, we used liposomal formulation of prednisolone disodium phosphate (LCL-PLP) to inhibit the protumor function of TAMs with the aim to sensitize the melanoma cells to the cytotoxic drug doxorubicin (DOX) to which human melanoma has intrinsic resistance. Consequently, we evaluated the in vivo effects of the concomitant administration of LCL-PLP and liposomal formulation of DOX (LCL-DOX) on B16.F10 melanoma growth and on the production of key molecular markers for tumor development. Our results demonstrated that the concomitant administration of LCL-PLP and LCL-DOX induced a strong inhibition of tumor growth, primarily by inhibiting TAMs-mediated angiogenesis as well as the tumor production of MMP-2 and AP-1. Moreover, our data suggested that the combined therapy also affected TME as the number of infiltrated macrophages in melanoma microenvironment was reduced significantly.

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Doxorubicin inhibits PD-L1 expression by enhancing TTP-mediated decay of PD-L1 mRNA in cancer cells

Cited by 22 publications

References 23 publications

TARBP2 promotes tumor angiogenesis and metastasis by destabilizing antiangiogenic factor mRNAs

TARBP2 promotes tumor angiogenesis and metastasis by destabilizing antiangiogenic factor mRNAs

Tristetraprolin, a Potential Safeguard Against Carcinoma: Role in the Tumor Microenvironment

Overcoming Intrinsic Doxorubicin Resistance in Melanoma by Anti-Angiogenic and Anti-Metastatic Effects of Liposomal Prednisolone Phosphate on Tumor Microenvironment

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