Small Molecule Activation of PKM2 in Cancer Cells Induces Serine Auxotrophy

Overview

Journal Chem Biol

Publisher Elsevier

Specialties Biochemistry
Biology
Chemistry

Date 2012 Sep 25

PMID 22999886

Citations 94

Authors

Charles Kung

Jeff Hixon

Sung Choe

Kevin Marks

Stefan Gross

Erin Murphy

Byron DeLaBarre

Giovanni Cianchetta

Shalini Sethumadhavan

Xiling Wang

Shunqi Yan

Yi Gao

Cheng Fang

Wentao Wei

Fan Jiang

Shaohui Wang

Kevin Qian

Jeff Saunders

Ed Driggers

Hin Koon Woo

Kaiko Kunii

Stuart Murray

Hua Yang

Katharine Yen

Wei Liu

Lewis C Cantley

Matthew G Vander Heiden

Shinsan M Su

Shengfang Jin

Francesco G Salituro

Lenny Dang

Affiliations

Soon will be listed here.

Abstract

Proliferating tumor cells use aerobic glycolysis to support their high metabolic demands. Paradoxically, increased glycolysis is often accompanied by expression of the lower activity PKM2 isoform, effectively constraining lower glycolysis. Here, we report the discovery of PKM2 activators with a unique allosteric binding mode. Characterization of how these compounds impact cancer cells revealed an unanticipated link between glucose and amino acid metabolism. PKM2 activation resulted in a metabolic rewiring of cancer cells manifested by a profound dependency on the nonessential amino acid serine for continued cell proliferation. Induction of serine auxotrophy by PKM2 activation was accompanied by reduced carbon flow into the serine biosynthetic pathway and increased expression of high affinity serine transporters. These data support the hypothesis that PKM2 expression confers metabolic flexibility to cancer cells that allows adaptation to nutrient stress.

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