CYP27A1-dependent anti-melanoma activity of limonoid natural products targets mitochondrial metabolism

Hyelim Cho; Qiong Shen; Lydia H Zhang; Mikiko Okumura; Akinori Kawakami; Jessi Ambrose; Frederic Sigoillot; Howard R Miller; Scott Gleim; Amanda Cobos-Correa; Ying Wang; Philippe Piechon; Guglielmo Roma; Fabian Eggimann; Charles Moore; Peter Aspesi Jr; Felipa A Mapa; Heather Burks; Nathan T Ross; Philipp Krastel; Marc Hild; Thomas J Maimone; David E Fisher; Daniel K Nomura; John A Tallarico; Stephen M Canham; Jeremy L Jenkins; William C Forrester

doi:10.1016/j.chembiol.2021.03.004

CYP27A1-dependent anti-melanoma activity of limonoid natural products targets mitochondrial metabolism

Cell Chem Biol. 2021 Oct 21;28(10):1407-1419.e6. doi: 10.1016/j.chembiol.2021.03.004. Epub 2021 Mar 31.

Authors

Hyelim Cho¹, Qiong Shen¹, Lydia H Zhang², Mikiko Okumura², Akinori Kawakami³, Jessi Ambrose¹, Frederic Sigoillot¹, Howard R Miller¹, Scott Gleim¹, Amanda Cobos-Correa⁴, Ying Wang⁴, Philippe Piechon⁴, Guglielmo Roma⁴, Fabian Eggimann⁴, Charles Moore⁴, Peter Aspesi Jr¹, Felipa A Mapa¹, Heather Burks¹, Nathan T Ross¹, Philipp Krastel⁴, Marc Hild¹, Thomas J Maimone², David E Fisher³, Daniel K Nomura⁵, John A Tallarico⁶, Stephen M Canham⁶, Jeremy L Jenkins⁷, William C Forrester⁸

Affiliations

¹ Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA.
² Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA 94720, USA.
³ Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁴ Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, 4056 Basel, Switzerland.
⁵ Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA; Innovative Genomics Institute, Berkeley, CA 94720, USA.
⁶ Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA 94720, USA.
⁷ Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: jeremy.jenkins@novartis.com.
⁸ Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: william.forrester@novartis.com.

Abstract

Three limonoid natural products with selective anti-proliferative activity against BRAF(V600E) and NRAS(Q61K)-mutation-dependent melanoma cell lines were identified. Differential transcriptome analysis revealed dependency of compound activity on expression of the mitochondrial cytochrome P450 oxidase CYP27A1, a transcriptional target of melanogenesis-associated transcription factor (MITF). We determined that CYP27A1 activity is necessary for the generation of a reactive metabolite that proceeds to inhibit cellular proliferation. A genome-wide small interfering RNA screen in combination with chemical proteomics experiments revealed gene-drug functional epistasis, suggesting that these compounds target mitochondrial biogenesis and inhibit tumor bioenergetics through a covalent mechanism. Our work suggests a strategy for melanoma-specific targeting by exploiting the expression of MITF target gene CYP27A1 and inhibiting mitochondrial oxidative phosphorylation in BRAF mutant melanomas.

Keywords: BRAF; CYP27A1; MITF; cancer metabolism; melanoma; mitochondrial complex I; natural products; oncology; oxidative phosphorylation; prodrug.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Biological Products / chemistry
Biological Products / metabolism
Biological Products / pharmacology
Biological Products / therapeutic use
Cell Line, Tumor
Cell Proliferation / drug effects
Cholestanetriol 26-Monooxygenase / antagonists & inhibitors
Cholestanetriol 26-Monooxygenase / genetics
Cholestanetriol 26-Monooxygenase / metabolism*
Humans
Limonins / chemistry
Limonins / metabolism
Limonins / pharmacology*
Limonins / therapeutic use
Melanoma / drug therapy
Melanoma / pathology
Microphthalmia-Associated Transcription Factor / genetics
Microphthalmia-Associated Transcription Factor / metabolism
Mitochondria / drug effects*
Mitochondria / metabolism
Oxidative Phosphorylation / drug effects
Promoter Regions, Genetic
Protein Binding
Proto-Oncogene Proteins B-raf / antagonists & inhibitors
Proto-Oncogene Proteins B-raf / genetics
Proto-Oncogene Proteins B-raf / metabolism
RNA Interference
RNA, Small Interfering / metabolism

Substances

Antineoplastic Agents
Biological Products
Limonins
MITF protein, human
Microphthalmia-Associated Transcription Factor
RNA, Small Interfering
CYP27A1 protein, human
Cholestanetriol 26-Monooxygenase
Proto-Oncogene Proteins B-raf

Abstract

Publication types

MeSH terms

Substances

Grants and funding