Cyclin D1 restrains oncogene-induced autophagy by regulating the AMPK–LKB1 signaling axis

Mathew C. Casimiro; Gabriele Di Sante; Agnese Di Rocco; Emanuele Loro; Claudia Pupo; Timothy G. Pestell; Sara Bisetto; Marco A. Velasco-Velázquez; Xuanmao Jiao; Zhiping Li; Christine M. Kusminski; Erin L. Seifert; Chenguang Wang; Daniel Ly; Bin Zheng; Che Hung Shen; Philipp E. Scherer; Richard G. Pestell

doi:10.1158/0008-5472.CAN-16-0425

Cyclin D1 restrains oncogene-induced autophagy by regulating the AMPK–LKB1 signaling axis

Mathew C. Casimiro
, Gabriele Di Sante
, Agnese Di Rocco
, Emanuele Loro
, Claudia Pupo
, Timothy G. Pestell
, Sara Bisetto
, Marco A. Velasco-Velázquez
, Xuanmao Jiao
, Zhiping Li
, Christine M. Kusminski
, Erin L. Seifert
, Chenguang Wang
, Daniel Ly
, Bin Zheng
, Che Hung Shen
, Philipp E. Scherer
, Richard G. Pestell

Research output: Contribution to journal › Article › peer-review

59 Citations (Scopus)

Abstract

Autophagy activated after DNA damage or other stresses mitigates cellular damage by removing damaged proteins, lipids, and organelles. Activation of the master metabolic kinase AMPK enhances autophagy. Here we report that cyclin D1 restrains autophagy by modulating the activation of AMPK. In cell models of human breast cancer or in a cyclin D1–deficient model, we observed a cyclin D1–mediated reduction in AMPK activation. Mechanistic investigations showed that cyclin D1 inhibited mitochondrial function, promoted glycolysis, and reduced activation of AMPK (pT172), possibly through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1. Our findings suggest how AMPK activation by cyclin D1 may couple cell proliferation to energy homeostasis.

Original language	English
Pages (from-to)	3391-3405
Number of pages	15
Journal	Cancer Research
Volume	77
Issue number	13
DOIs	https://doi.org/10.1158/0008-5472.CAN-16-0425
Publication status	Published - 1 Jul 2017
Externally published	Yes

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1158/0008-5472.CAN-16-0425

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Casimiro, M. C., Di Sante, G., Di Rocco, A., Loro, E., Pupo, C., Pestell, T. G., Bisetto, S., Velasco-Velázquez, M. A., Jiao, X., Li, Z., Kusminski, C. M., Seifert, E. L., Wang, C., Ly, D., Zheng, B., Shen, C. H., Scherer, P. E., & Pestell, R. G. (2017). Cyclin D1 restrains oncogene-induced autophagy by regulating the AMPK–LKB1 signaling axis. Cancer Research, 77(13), 3391-3405. https://doi.org/10.1158/0008-5472.CAN-16-0425

@article{e15185710e5c43f993ba6b4d1c9346c5,

title = "Cyclin D1 restrains oncogene-induced autophagy by regulating the AMPK–LKB1 signaling axis",

abstract = "Autophagy activated after DNA damage or other stresses mitigates cellular damage by removing damaged proteins, lipids, and organelles. Activation of the master metabolic kinase AMPK enhances autophagy. Here we report that cyclin D1 restrains autophagy by modulating the activation of AMPK. In cell models of human breast cancer or in a cyclin D1–deficient model, we observed a cyclin D1–mediated reduction in AMPK activation. Mechanistic investigations showed that cyclin D1 inhibited mitochondrial function, promoted glycolysis, and reduced activation of AMPK (pT172), possibly through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1. Our findings suggest how AMPK activation by cyclin D1 may couple cell proliferation to energy homeostasis.",

author = "Casimiro, \{Mathew C.\} and \{Di Sante\}, Gabriele and \{Di Rocco\}, Agnese and Emanuele Loro and Claudia Pupo and Pestell, \{Timothy G.\} and Sara Bisetto and Velasco-Vel{\'a}zquez, \{Marco A.\} and Xuanmao Jiao and Zhiping Li and Kusminski, \{Christine M.\} and Seifert, \{Erin L.\} and Chenguang Wang and Daniel Ly and Bin Zheng and Shen, \{Che Hung\} and Scherer, \{Philipp E.\} and Pestell, \{Richard G.\}",

note = "Funding Information: This work was supported in part by NIH grants (1R01CA137494, R01CA132115, R01CA086072 to R.G. Pestell), the Sidney Kimmel Cancer Center NIH Cancer Center Core grant P30CA056036 to R.G. Pestell, generous grants from The Breast Cancer Research Foundation to R.G. Pestell, and the Dr. Ralph and Marian C. Falk Medical Research Trust to R.G. Pestell, a grant from the Pennsylvania Department of Health to R.G. Pestell, and an American-Italian Cancer Foundation Post-doctoral Research Fellowship to G. Di Sante. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Publisher Copyright: {\textcopyright}2017 AACR.",

year = "2017",

month = jul,

day = "1",

doi = "10.1158/0008-5472.CAN-16-0425",

language = "English",

volume = "77",

pages = "3391--3405",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "13",

}

Casimiro, MC, Di Sante, G, Di Rocco, A, Loro, E, Pupo, C, Pestell, TG, Bisetto, S, Velasco-Velázquez, MA, Jiao, X, Li, Z, Kusminski, CM, Seifert, EL, Wang, C, Ly, D, Zheng, B, Shen, CH, Scherer, PE & Pestell, RG 2017, 'Cyclin D1 restrains oncogene-induced autophagy by regulating the AMPK–LKB1 signaling axis', Cancer Research, vol. 77, no. 13, pp. 3391-3405. https://doi.org/10.1158/0008-5472.CAN-16-0425

TY - JOUR

T1 - Cyclin D1 restrains oncogene-induced autophagy by regulating the AMPK–LKB1 signaling axis

AU - Casimiro, Mathew C.

AU - Di Sante, Gabriele

AU - Di Rocco, Agnese

AU - Loro, Emanuele

AU - Pupo, Claudia

AU - Pestell, Timothy G.

AU - Bisetto, Sara

AU - Velasco-Velázquez, Marco A.

AU - Jiao, Xuanmao

AU - Li, Zhiping

AU - Kusminski, Christine M.

AU - Seifert, Erin L.

AU - Wang, Chenguang

AU - Ly, Daniel

AU - Zheng, Bin

AU - Shen, Che Hung

AU - Scherer, Philipp E.

AU - Pestell, Richard G.

N1 - Funding Information: This work was supported in part by NIH grants (1R01CA137494, R01CA132115, R01CA086072 to R.G. Pestell), the Sidney Kimmel Cancer Center NIH Cancer Center Core grant P30CA056036 to R.G. Pestell, generous grants from The Breast Cancer Research Foundation to R.G. Pestell, and the Dr. Ralph and Marian C. Falk Medical Research Trust to R.G. Pestell, a grant from the Pennsylvania Department of Health to R.G. Pestell, and an American-Italian Cancer Foundation Post-doctoral Research Fellowship to G. Di Sante. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Publisher Copyright: ©2017 AACR.

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Autophagy activated after DNA damage or other stresses mitigates cellular damage by removing damaged proteins, lipids, and organelles. Activation of the master metabolic kinase AMPK enhances autophagy. Here we report that cyclin D1 restrains autophagy by modulating the activation of AMPK. In cell models of human breast cancer or in a cyclin D1–deficient model, we observed a cyclin D1–mediated reduction in AMPK activation. Mechanistic investigations showed that cyclin D1 inhibited mitochondrial function, promoted glycolysis, and reduced activation of AMPK (pT172), possibly through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1. Our findings suggest how AMPK activation by cyclin D1 may couple cell proliferation to energy homeostasis.

AB - Autophagy activated after DNA damage or other stresses mitigates cellular damage by removing damaged proteins, lipids, and organelles. Activation of the master metabolic kinase AMPK enhances autophagy. Here we report that cyclin D1 restrains autophagy by modulating the activation of AMPK. In cell models of human breast cancer or in a cyclin D1–deficient model, we observed a cyclin D1–mediated reduction in AMPK activation. Mechanistic investigations showed that cyclin D1 inhibited mitochondrial function, promoted glycolysis, and reduced activation of AMPK (pT172), possibly through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1. Our findings suggest how AMPK activation by cyclin D1 may couple cell proliferation to energy homeostasis.

UR - https://www.scopus.com/pages/publications/85023771902

U2 - 10.1158/0008-5472.CAN-16-0425

DO - 10.1158/0008-5472.CAN-16-0425

M3 - Article

C2 - 28522753

AN - SCOPUS:85023771902

SN - 0008-5472

VL - 77

SP - 3391

EP - 3405

JO - Cancer Research

JF - Cancer Research

IS - 13

ER -

Cyclin D1 restrains oncogene-induced autophagy by regulating the AMPK–LKB1 signaling axis

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