Increased Serine and One-Carbon Pathway Metabolism by PKCλ/l Deficiency Promotes Neuroendocrine Prostate Cancer

被引：132

作者：

Reina-Campos, Miguel ^{[1
,2
]}

Linares, Juan F. ^{[1
]}

Duran, Angeles ^{[1
]}

Cordes, Thekla ^{[3
]}

L'Hermitte, Antoine ^{[1
]}

Badur, Mehmet G. ^{[3
]}

Bhangoo, Munveer S. ^{[4
]}

Thorson, Phataraporn K. ^{[5
]}

Richards, Alicia ^{[6
]}

Rooslid, Tarmo ^{[7
]}

Garcia-Olmo, Dolores C. ^{[8
]}

Nam-Cha, Syongh Y. ^{[9
]}

Salinas-Sanchez, Antonio S. ^{[10
]}

Eng, Ken ^{[11
]}

Beltran, Himisha ^{[12
]}

Scott, David A. ^{[13
]}

Metallo, Christian M. ^{[3
]}

Moscat, Jorge ^{[1
]}

Diaz-Meco, Maria T. ^{[1
]}

机构：

[1] Sanford Burnham Prebys Med Discovery Inst, Canc Metab & Signaling Networks Program, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA

[2] Sanford Burnham Prebys Grad Sch Biomed Sci, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA

[3] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA

[4] Div Hematol Oncol Scripps Clin, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA

[5] Scripps Clin Med Grp, Depatment Pathol, 10666 Torrey Pines Rd, La Jolla, CA 92037 USA

[6] Sanford Burnham Prebys Med Discovery Inst, Prote Facil, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA

[7] Sanford Burnham Prebys Med Discovery Inst, Conrad Prebys Ctr Drug Discovery, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA

[8] IRBLLEIDA, CREBA, Lleida 25138, Spain

[9] Univ Castilla La Mancha, Sch Med, Pathol Dept, Res Unit Biobank, Albacete 02006, Spain

[10] Univ Hosp Complex Albacete, Urol Dept, Res Unit, Sch Med, Albacete 02006, Spain

[11] Weill Cornell Med, Dept Computat Biomed, New York, NY 10065 USA

[12] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[13] Sanford Burnham Prebys Med Discovery Inst, Canc Metab Core, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA

来源：

CANCER CELL | 2019年 / 35卷 / 03期

关键词：

LINEAGE PLASTICITY; INCREASED SURVIVAL; PROLIFERATION; TUMORIGENESIS; INFLAMMATION; GENERATION; RESISTANCE; COOPERATE; RAGULATOR; NETWORK;

D O I：

10.1016/j.ccell.2019.01.018

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)lambda/l is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKC lambda/l deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.

引用

页码：385 / +

页数：25

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