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

169 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 (US)
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 - Mar 9 2015
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

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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

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

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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.}",

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year = "2015",

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

language = "English (US)",

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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.

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

Abstract

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