An RGDKGE-Containing Cryptic Collagen Fragment Regulates Phosphorylation of Large Tumor Suppressor Kinase-1 and Controls Ovarian Tumor Growth by a Yes-Associated Protein–Dependent Mechanism

Han, Xianghua; Caron, Jennifer M.; Lary, Christine W.; Sathyanarayana, Pradeep; Vary, Calvin P.H.; Brooks, Peter C.

doi:10.1016/j.ajpath.2020.11.009

Cited by 1 publication

(10 citation statements)

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“…Tumor cells were suspended in adhesion buffer (DMEM) containing 1 mM MgCl 2 , 0.2 mM MnCl 2 and 0.5% BSA, and 1x10 5 cells were added to the wells in the presence of 100 µg/ml of Mab XL313, anti-β3 integrin antibody, anti-β1 integrin antibody or non-specific control IgG and allowed to bind for 10-20 min at 37˚C. Non-attached cells were removed and attached cells were stained with crystal violet as previously described (10,31). Cell binding was quantified by measuring the optical density of eluted dye as previously described (10,31).…”

Section: Cell Binding Assaysmentioning

confidence: 99%

“…Non-attached cells were removed and attached cells were stained with crystal violet as previously described (10,31). Cell binding was quantified by measuring the optical density of eluted dye as previously described (10,31). Cell binding assays were performed at least 3 times with triplicate wells per condition.…”

Section: Cell Binding Assaysmentioning

confidence: 99%

“…Tumor growth assays. Tumor growth assays were performed as previously described (10,30). Briefly, mice were injected subcutaneously with either 3.5x10 5 Β16F10 cells, non-target Β16F10 cells, 3.5x10 6 PD-L1 knock-down Β16F10 (N=8-10 C57BL/6 mice per condition) or 3x10 5 4T1 mammary carcinoma cells resuspended in 100 µl of sterile PBS.…”

Section: Cell Binding Assaysmentioning

confidence: 99%

“…Selectively targeting the secreted RGDKGE-containing collagen fragment reduces PD-L1 levels. Previous studies indicated that blocking β3 integrin-mediated interactions with the RGDKGE-containing collagen fragment inhibits YAP nuclear accumulation in endothelial cells as well as ovarian carcinoma cells (9,10). Notably, both β3 integrin and YAP have been shown to regulate the levels of the immune checkpoint molecule PD-L1 (11)(12)(13).…”

Section: Detection Of the Rgdkge-containing Collagen Fragment In Mali...mentioning

confidence: 99%

“…This 16 kDa RGDKGE-containing collagen fragment binds to and activates integrin αvβ3 expressed on vascular endothelial cells leading to enhanced nuclear accumulation of the Yes-associated protein (YAP) (9). Recently, it was also demonstrated by the authors that ovarian carcinoma cell interactions with this collagen fragment suppressed phosphorylation of the hippo effector kinase LATS1, and reduced the inhibitory phosphorylation of YAP which ultimately led to its nuclear accumulation (10). Selectively targeting this collagen fragment in ovarian carcinoma cells inhibited YAP nuclear accumulation and suppressed tumor growth in vivo (10).…”

Section: Introductionmentioning

confidence: 99%

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Targeting the secreted RGDKGE collagen fragment reduces PD‑L1 by a proteasome‑dependent mechanism and inhibits tumor growth

et al. 2023

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Structural alterations of collagen impact signaling that helps control tumor progression and the responses to therapeutic intervention. Integrins represent a class of receptors that include members that mediate collagen signaling. However, a strategy of directly targeting integrins to control tumor growth has demonstrated limited activity in the clinical setting. New molecular understanding of integrins have revealed that these receptors can regulate both pro-and anti-tumorigenic functions in a cell type-dependent manner. Therefore, designing strategies that block pro-tumorigenic signaling, without impeding anti-tumorigenic functions, may lead to development of more effective therapies. In the present study, evidence was provided for a novel signaling cascade in which β3-integrin-mediated binding to a secreted RGDKGE-containing collagen fragment stimulates an autocrine-like signaling pathway that differentially governs the activity of both YAP and (protein kinase-A) PKA, ultimately leading to alterations in the levels of immune checkpoint molecule PD-L1 by a proteasome dependent mechanism. Selectively targeting this collagen fragment, reduced nuclear YAP levels, and enhanced PKA and proteasome activity, while also exhibiting significant antitumor activity in vivo. The present findings not only provided new mechanistic insight into a previously unknown autocrine-like signaling pathway that may provide tumor cells with the ability to regulate PD-L1, but our findings may also help in the development of more effective strategies to control pro-tumorigenic β3-integrin signaling without disrupting its tumor suppressive functions in other cellular compartments.

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