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ROLE OF THE SLC35B2-TPST2 AXIS OF TYROSINE SULFATION IN THE DEVELOPMENT AND METASTASIS OF PANCREATIC DUCTAL ADENOCARCINOMA

Cai, Xinran (2023) ROLE OF THE SLC35B2-TPST2 AXIS OF TYROSINE SULFATION IN THE DEVELOPMENT AND METASTASIS OF PANCREATIC DUCTAL ADENOCARCINOMA. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease and the fourth leading cause of cancer deaths in the United States. Tyrosine sulfation, catalyzed by the tyrosylprotein sulfotransferase 2 (TPST2), is a post-translational modification essential for protein-protein interactions and cellular functions. SLC35B2 is a key transporter that transports the universal sulfate donor 3’-phosphoadenosine 5’-phosphosulfate (PAPS) into the Golgi apparatus where the protein sulfation occurs. In this study, we found that the expression of SLC35B2 was upregulated in PDAC patients and in a mouse model of PDAC, and the upregulation of SLC35B2 was correlated with poor patient survival. Knockdown of SLC35B2 or TPST2, or pharmacological inhibition of sulfation inhibited PDAC cell proliferation and migration in vitro. In vivo, TPST2 deficient PDAC MIA PaCa-2 cells exhibited delayed xenograft tumor growth in athymic nude mice. Orthotopic inoculation of Tpst2 KO KPC cells into C57BL/6J mice showed smaller primary tumor, decreased local invasion, and improved survival. Mice given tail-vein injections of Tpst2 KO KPC cells also showed attenuated lung metastasis. Mechanistically, we found that the integrin ITGB4 expression was decreased by silencing TPST2 or treatment with the sulfation inhibitor sodium chlorate. ITGB4 is a novel substrate of TPST2, and inhibition of sulfation destabilizes ITGB4 protein, which may have favored the suppression of metastasis. We propose that targeting the SLC35B2-TPST2 axis of tyrosine sulfation represents a novel approach for therapeutic intervention of PDAC.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Cai, Xinranxic74@pitt.eduxic74
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorXie, Wen
Committee ChairYang, Da
Committee MemberLi, Song
Committee MemberJohnson, Paul A.
Committee MemberTang, Daolin
Date: 3 May 2023
Date Type: Publication
Defense Date: 9 August 2022
Approval Date: 3 May 2023
Submission Date: 14 April 2023
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 83
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: pancreatic cancer, post-translational modification, sulfation
Date Deposited: 03 May 2023 13:45
Last Modified: 03 May 2023 13:45
URI: http://d-scholarship.pitt.edu/id/eprint/44566

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