박준형 (Baylor College of Medicine) | 한빛사논문 > 한빛사

한빛사논문

조회297

박준형Junhyoung Park

Baylor College of Medicine

Cell Rep. Med., February 10, 2025 | https://doi.org/10.1016/j.xcrm.2025.101941 Biguanides antithetically regulate tumor properties by the dose-dependent mitochondrial reprogramming-driven c-Src pathway

Jun Hyoung Park,¹Kwang Hwa Jung,¹ Dongya Jia,² Sukjin Yang,¹ Kuldeep S. Attri,¹ Songyeon Ahn,¹ Divya Murthy,1 Tagari Samanta,¹ Debasmita Dutta,¹ Meron Ghidey,¹ Somik Chatterjee,¹ Seung Yeop Han,¹ Diego A. Pedroza,³ Abha Tiwari,¹ Joyce V. Lee,⁴ Caitlin Davis,⁴ Shuting Li,⁴ Vasanta Putluri,^3,6 Chad J. Creighton,^5,6 Nagireddy Putluri,^3,6 Lacey E. Dobrolecki,³ Michael T. Lewis,^3,6 Jeffrey M. Rosen,^3,6Jose´ N. Onuchic,²Andrei Goga,⁴ and Benny Abraham Kaipparettu ^1,6,7,*

¹Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
²Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA
³Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
⁴Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, CA 94143, USA
⁵Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
⁶Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
⁷Lead contact

^*Corresponding author: correspondence to Benny Abraham Kaipparettu

Abstract

The biguanide metformin attenuates mitochondrial oxidation and is proposed as an anti-cancer therapy. However, recent clinical studies suggest increased proliferation and fatty acid β-oxidation (FAO) in a subgroup of patients with breast cancer (BC) after metformin therapy. Considering that FAO can activate Src kinase in aggressive triple-negative BC (TNBC), we postulate that low-dose biguanide-driven AMPK-ACC-FAO signaling may activate the Src pathway in TNBC. The low bioavailability of metformin in TNBC xenografts mimics metformin’s in vitro low-dose effect. Pharmacological or genetic inhibition of FAO significantly enhances the anti-tumor properties of biguanides. Lower doses of biguanides induce and higher doses suppress Src signaling. Dasatinib and metformin synergistically inhibit TNBC patient-derived xenograft growth, but not in high-fat diet-fed mice. This combination also suppresses TNBC metastatic progression. A combination of biguanides with Src inhibitors provides synergy to target metastatic TNBC suffering with limited treatment options.

논문정보

형식Research article
게재일2025년 02월 (BRIC 등록일 2025-02-12)
연구진국외 연구진
분야 생명과학 > 노화/암생물학

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