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Centchroman prevents metastatic colonization of breast cancer cells and disrupts angiogenesis via inhibition of RAC1/PAK1/β-catenin signaling axis.

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Relation http://ir.cftri.com/14504/
https://doi.org/10.1016/j.lfs.2020.117976
 
Title Centchroman prevents metastatic colonization of breast cancer cells and disrupts angiogenesis via inhibition of RAC1/PAK1/β-catenin signaling axis.
 
Creator Sajid, Khan
Samriddhi, Shukla
Mohammad, Farhan
Sonam, Sinha
Amar Deep, Lakra
Dhanamjai, Penta
Anbarasu, K.
Meeran, Syed Musthapa
 
Subject 09 Human Physiology
 
Description Aims

We have previously reported that Centchroman (CC), an oral contraceptive drug, inhibits breast cancer progression and metastasis. In this study, we investigated whether CC inhibits local invasion of tumor cells and/or their metastatic colonization with detailed underlying mechanisms.
Main methods

The effect of CC on the experimental metastasis and spontaneous metastasis was demonstrated by using tail-vein and orthotopic 4T1-syngeneic mouse tumor models, respectively. The anti-angiogenic potential of CC was evaluated using well established in vitro and in vivo models. The role of RAC1/PAK1/β-catenin signaling axis in the metastasis was investigated and validated using siRNA-mediated knockdown of PAK1 as well as by pharmacological PAK1-inhibitor.
Key findings

The oral administration of CC significantly suppressed the formation of metastatic lung nodules in the 4T1-syngeneic orthotopic as well as experimental metastatic models. More importantly, CC treatment suppressed the tube formation and migration capacities of human umbilical vein endothelial cells (HUVEC) and inhibited pre-existing vasculature as well as the formation of neovasculature. The suppression of migration and invasion capacities of metastatic breast cancer cells upon CC treatment was associated with the inhibition of small GTPases (Rac1 and Cdc42) concomitant with the downregulation of PAK1 and downstream β-catenin signaling. In addition, CC upregulated the expression of miR-145, which is known to target PAK1.
Significance

This study warrants the repurposing of CC as a potential therapeutic agent against metastatic breast cancer.
 
Date 2020
 
Type Article
PeerReviewed
 
Format pdf
 
Language en
 
Identifier http://ir.cftri.com/14504/1/Life%20Sciences%202020.pdf
Sajid, Khan and Samriddhi, Shukla and Mohammad, Farhan and Sonam, Sinha and Amar Deep, Lakra and Dhanamjai, Penta and Anbarasu, K. and Meeran, Syed Musthapa (2020) Centchroman prevents metastatic colonization of breast cancer cells and disrupts angiogenesis via inhibition of RAC1/PAK1/β-catenin signaling axis. Life Sciences, 256. p. 117976. ISSN 0024-3205