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

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

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Abstract

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.

Item Type:	Article
Uncontrolled Keywords:	Breast cancer Centchroman Metastasis Angiogenesis PAK1
Subjects:	600 Technology > 01 Medical sciences > 09 Human Physiology
Divisions:	Dept. of Biochemistry
Depositing User:	Food Sci. & Technol. Information Services
Date Deposited:	05 Oct 2020 09:22
Last Modified:	05 Oct 2020 09:22
URI:	http://ir.cftri.res.in/id/eprint/14504

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