Cell Rep. 2019 Dec 3;29(10):3009-3018.e4. doi: 10.1016/j.celrep.2019.11.007. | PubMed

Hamidullah Khan¹, Ashish Anshu¹, Aman Prasad¹, Sushmita Roy¹, Justin Jeffery², Wasakorn Kittipongdaja³, David T Yang⁴, Stefan M Schieke⁵

1. Department of Dermatology, University of Wisconsin-Madison, Madison, WI 53706, USA.
2. Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA.
3. Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
4. Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
5. Department of Dermatology, University of Wisconsin-Madison, Madison, WI 53706, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA. Electronic address: schieke@wisc.edu.

Abstract

Metabolic flexibility allows cells to adapt to various environments and limits the efficacy of metabolic drugs. Therapeutic targeting of cancer metabolism relies on defining limiting requirements and vulnerabilities in the highly dynamic metabolic network. Here, we characterize the metabolic reprogramming and identify cancer-specific metabolic vulnerabilities in response to the pharmacological inhibition of mitochondrial complex I. Our work reveals the adaptation mechanism in malignant lymphocytes providing resistance against the biguanides phenformin and metformin by transcriptionally reprogramming glucose metabolism. Metabolic adaptation to complex I inhibition is mediated by mitochondrial reactive oxygen species (mROS) serving as a mitochondrial stress signal activating hypoxia-inducible factor-1a (HIF-1a). Inhibition of the mROS/HIF-1a axis through antioxidants or direct suppression of HIF-1a selectively disrupts metabolic adaptation and survival during complex I dysfunction in malignant lymphocytes. Our results identify HIF-1a signaling as a critical factor in resistance against biguanide-induced mitochondrial dysfunction, allowing selective targeting of metabolic pathways in leukemia and lymphoma.

Presented By Hamidullah Khan