The role of XIAP and XIAP-antagonization through mitochondria in melanoma metastasis
Cell Biology
Final Report Abstract
The longstanding goal of this project was to decipher the pathophysiologic role and therapeutic potential of XIAP in melanoma progression. Elevated expression of XIAP has been detected in various types of cancer, including melanoma, and frequently correlates with the resistance to anti-cancer therapy. Although found in the advanced stage of the disease, we demonstrated that elevated XIAP expression alone could not serve as a predictive marker of chemoresistance. Recent discoveries indicated that XIAP is involved in several additional cellular activities independent of its caspase inhibitory function. Using two separate mouse cancer models with XIAP deficiency and overexpression generated in our studies, the data obtained showed that XIAP promotes tumor progression but does not interfere with the apoptotic propensity of tumor cells. Further ongoing studies aim to decipher how elevated XIAP expression in mice interferes with tumor progression. Therapeutic antagonization of XIAP by Birinapant in mouse bearing melanoma tumors significantly reduced tumor growth. Our detailed analyses, however, showed that the antitumor activity is based on the vascular destruction within a tumor exposed to Birinapant. Our data collectively indicated that Birinapant efficiently antagonized cIAP1 and cIAP2 in endothelial cells which in turn increased their susceptibility to inflammatory tumor environment containing TNF. This novel targeting approach could be of clinical value in controlling pathological neoangiogenesis under inflammatory conditions while sparing blood vessels under average condition. Our detailed biochemical and cell biological approaches showed that antagonization of XIAP using SMAC mimetics or specific XIAP deletion (knock-down or knock-out) caused reduced invasion of melanoma cell lines in dermal equivalents. Furthermore, XIAP ablation/inhibition in melanoma cells reduced melanoma cells mediated vascular mimicry (VM) that would further support tumor vascularization. VM was mediated by the activity of the BIR3 and RING domain of XIAP suggesting the control of VM by an XIAP-mediated ubiquitination process. We provided additional evidence that XIAP expression correlates with the formation of the VM structures in malignant melanomas (patients) in vivo. Targeting XIAP in melanoma and its microenvironment may represent a possible therapeutic for melanoma progression and those melanomas overcoming vascular targeting therapies. Ongoing studies aim to address more in detail the molecular basis for the activity of XIAPs in the VM pathway that will allow the development of more specific targeting strategies to interfere with VM.
Publications
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(2015) IAP antagonization promotes the inflammatory destruction of vascular endothelium. EMBO reports 16(6):719-27
Witt A, Seeger J, Coutelle O, Zigrino P, Broxtermann P, Andree M, Brinkmann K, Juengst C, Schauss A, Wohlleber D, Knolle P, Krönke M, Mauch C, Schüll S and Kashkar H
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(2015) Regulation of the DNA Damage Response by Ubiquitin Conjugation. Front. Genet. 6:98
Brinkmann K, Schell M, Hoppe T, Kashkar H
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(2017) PARL mediates Smac proteolytic maturation in mitochondria to promote apoptosis. Nat. Cell Biol. 2017, 19:318–328
Saita S, Nolte H, Fiedler KU, Kashkar H, Venne AS, Zahedi RP, Krueger M, Langer M
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(2019) Elevated X-linked inhibitor of apoptosis protein (XIAP) expression uncovers detrimental prognosis in subgroups of neoadjuvant treated and T-cell rich esophageal adenocarcinoma. BMC Cancer 2019, 19(1):531
Schiffmann LM, Göbel H, Löser H, Schorn F, Werthenbach JP, Fuchs HF, Plum PS, Bludau M, Zander T, Schröder W, Bruns CJ, Kashkar H, Quaas A, Gebauer F
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(2019), The X-linked inhibitor of apoptosis protein (XIAP) is involved in melanoma invasion by regulating cell migration and survival. Cell Oncol (Dordr) 42(3):319-329
Ayachi O, Barlin M, Broxtermann PN, Kashkar H, Mauch C, Zigrino P
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(2019): Apoptosis-unrelated functions of XIAP in melanoma. Ph.D. Thesis, University of Cologne
Barlin M
