Regulation of Glutamine Carrier Proteins by RNF5 Determines Breast Cancer Response to ER Stress-Inducing Chemotherapies

Young Joo Jeon; Sihem Khelifa; Boris Ratnikov; David A. Scott; Yongmei Feng; Fabio Parisi; Chelsea Ruller; Eric Lau; Hyungsoo Kim; Laurence M. Brill; Tingting Jiang; David L. Rimm; Robert D. Cardiff; Gordon B. Mills; Jeffrey W. Smith; Andrei L. Osterman; Yuval Kluger; Ze'ev A. Ronai

doi:10.1016/j.ccell.2015.02.006

Regulation of Glutamine Carrier Proteins by RNF5 Determines Breast Cancer Response to ER Stress-Inducing Chemotherapies

Young Joo Jeon
, Sihem Khelifa
, Boris Ratnikov
, David A. Scott
, Yongmei Feng
, Fabio Parisi
, Chelsea Ruller
, Eric Lau
, Hyungsoo Kim
, Laurence M. Brill
, Tingting Jiang
, David L. Rimm
, Robert D. Cardiff
, Gordon B. Mills
, Jeffrey W. Smith
, Andrei L. Osterman
, Yuval Kluger
, Ze'ev A. Ronai

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

202 Scopus citations

Abstract

Many tumor cells are fueled by altered metabolism and increased glutamine (Gln) dependence. We identify regulation of the L-glutamine carrier proteins SLC1A5 and SLC38A2 (SLC1A5/38A2) by the ubiquitin ligase RNF5. Paclitaxel-induced ER stress to breast cancer (BCa) cells promotes RNF5 association, ubiquitination, and degradation of SLC1A5/38A2. This decreases Gln uptake, levels of TCA cycle components, mTOR signaling, and proliferation while increasing autophagy and cell death. Rnf5-deficient MMTV-PyMT mammary tumors were less differentiated and showed elevated SLC1A5 expression. Whereas RNF5 depletion in MDA-MB-231 cells promoted tumorigenesis and abolished paclitaxel responsiveness, SLC1A5/38A2 knockdown elicited opposing effects. Inverse RNF5^hi/SLC1A5/38A2^lo expression was associated with positive prognosis in BCa. Thus, RNF5 control of Gln uptake underlies BCa response to chemotherapies.

Original language	English
Pages (from-to)	354-369
Number of pages	16
Journal	Cancer Cell
Volume	27
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2015.02.006
State	Published - 9 Mar 2015
Externally published	Yes

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Jeon, Y. J., Khelifa, S., Ratnikov, B., Scott, D. A., Feng, Y., Parisi, F., Ruller, C., Lau, E., Kim, H., Brill, L. M., Jiang, T., Rimm, D. L., Cardiff, R. D., Mills, G. B., Smith, J. W., Osterman, A. L., Kluger, Y., & Ronai, Z. A. (2015). Regulation of Glutamine Carrier Proteins by RNF5 Determines Breast Cancer Response to ER Stress-Inducing Chemotherapies. Cancer Cell, 27(3), 354-369. https://doi.org/10.1016/j.ccell.2015.02.006

@article{7860949ad69844b3a6c2eebe64c1bf2f,

title = "Regulation of Glutamine Carrier Proteins by RNF5 Determines Breast Cancer Response to ER Stress-Inducing Chemotherapies",

abstract = "Many tumor cells are fueled by altered metabolism and increased glutamine (Gln) dependence. We identify regulation of the L-glutamine carrier proteins SLC1A5 and SLC38A2 (SLC1A5/38A2) by the ubiquitin ligase RNF5. Paclitaxel-induced ER stress to breast cancer (BCa) cells promotes RNF5 association, ubiquitination, and degradation of SLC1A5/38A2. This decreases Gln uptake, levels of TCA cycle components, mTOR signaling, and proliferation while increasing autophagy and cell death. Rnf5-deficient MMTV-PyMT mammary tumors were less differentiated and showed elevated SLC1A5 expression. Whereas RNF5 depletion in MDA-MB-231 cells promoted tumorigenesis and abolished paclitaxel responsiveness, SLC1A5/38A2 knockdown elicited opposing effects. Inverse RNF5hi/SLC1A5/38A2lo expression was associated with positive prognosis in BCa. Thus, RNF5 control of Gln uptake underlies BCa response to chemotherapies.",

author = "Jeon, \{Young Joo\} and Sihem Khelifa and Boris Ratnikov and Scott, \{David A.\} and Yongmei Feng and Fabio Parisi and Chelsea Ruller and Eric Lau and Hyungsoo Kim and Brill, \{Laurence M.\} and Tingting Jiang and Rimm, \{David L.\} and Cardiff, \{Robert D.\} and Mills, \{Gordon B.\} and Smith, \{Jeffrey W.\} and Osterman, \{Andrei L.\} and Yuval Kluger and Ronai, \{Ze'ev A.\}",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = mar,

day = "9",

doi = "10.1016/j.ccell.2015.02.006",

language = "English",

volume = "27",

pages = "354--369",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "3",

}

Jeon, YJ, Khelifa, S, Ratnikov, B, Scott, DA, Feng, Y, Parisi, F, Ruller, C, Lau, E, Kim, H, Brill, LM, Jiang, T, Rimm, DL, Cardiff, RD, Mills, GB, Smith, JW, Osterman, AL, Kluger, Y & Ronai, ZA 2015, 'Regulation of Glutamine Carrier Proteins by RNF5 Determines Breast Cancer Response to ER Stress-Inducing Chemotherapies', Cancer Cell, vol. 27, no. 3, pp. 354-369. https://doi.org/10.1016/j.ccell.2015.02.006

TY - JOUR

T1 - Regulation of Glutamine Carrier Proteins by RNF5 Determines Breast Cancer Response to ER Stress-Inducing Chemotherapies

AU - Jeon, Young Joo

AU - Khelifa, Sihem

AU - Ratnikov, Boris

AU - Scott, David A.

AU - Feng, Yongmei

AU - Parisi, Fabio

AU - Ruller, Chelsea

AU - Lau, Eric

AU - Kim, Hyungsoo

AU - Brill, Laurence M.

AU - Jiang, Tingting

AU - Rimm, David L.

AU - Cardiff, Robert D.

AU - Mills, Gordon B.

AU - Smith, Jeffrey W.

AU - Osterman, Andrei L.

AU - Kluger, Yuval

AU - Ronai, Ze'ev A.

PY - 2015/3/9

Y1 - 2015/3/9

N2 - Many tumor cells are fueled by altered metabolism and increased glutamine (Gln) dependence. We identify regulation of the L-glutamine carrier proteins SLC1A5 and SLC38A2 (SLC1A5/38A2) by the ubiquitin ligase RNF5. Paclitaxel-induced ER stress to breast cancer (BCa) cells promotes RNF5 association, ubiquitination, and degradation of SLC1A5/38A2. This decreases Gln uptake, levels of TCA cycle components, mTOR signaling, and proliferation while increasing autophagy and cell death. Rnf5-deficient MMTV-PyMT mammary tumors were less differentiated and showed elevated SLC1A5 expression. Whereas RNF5 depletion in MDA-MB-231 cells promoted tumorigenesis and abolished paclitaxel responsiveness, SLC1A5/38A2 knockdown elicited opposing effects. Inverse RNF5hi/SLC1A5/38A2lo expression was associated with positive prognosis in BCa. Thus, RNF5 control of Gln uptake underlies BCa response to chemotherapies.

AB - Many tumor cells are fueled by altered metabolism and increased glutamine (Gln) dependence. We identify regulation of the L-glutamine carrier proteins SLC1A5 and SLC38A2 (SLC1A5/38A2) by the ubiquitin ligase RNF5. Paclitaxel-induced ER stress to breast cancer (BCa) cells promotes RNF5 association, ubiquitination, and degradation of SLC1A5/38A2. This decreases Gln uptake, levels of TCA cycle components, mTOR signaling, and proliferation while increasing autophagy and cell death. Rnf5-deficient MMTV-PyMT mammary tumors were less differentiated and showed elevated SLC1A5 expression. Whereas RNF5 depletion in MDA-MB-231 cells promoted tumorigenesis and abolished paclitaxel responsiveness, SLC1A5/38A2 knockdown elicited opposing effects. Inverse RNF5hi/SLC1A5/38A2lo expression was associated with positive prognosis in BCa. Thus, RNF5 control of Gln uptake underlies BCa response to chemotherapies.

UR - https://www.scopus.com/pages/publications/84924250667

U2 - 10.1016/j.ccell.2015.02.006

DO - 10.1016/j.ccell.2015.02.006

M3 - Article

C2 - 25759021

AN - SCOPUS:84924250667

SN - 1535-6108

VL - 27

SP - 354

EP - 369

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

Regulation of Glutamine Carrier Proteins by RNF5 Determines Breast Cancer Response to ER Stress-Inducing Chemotherapies

Abstract

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