Abstract
Cellular senescence is a fundamental biological process that has profound implications in cancer development and therapeutics, but the underlying mechanisms remain elusive. Here we show that carnitine palmitoyltransferase 1C (CPT1C), an enzyme that catalyzes carnitinylation of fatty acids for transport into mitochondria for β-oxidation, plays a major role in the regulation of cancer cell senescence through mitochondria-associated metabolic reprograming. Metabolomics analysis suggested alterations in mitochondria activity, as revealed by the marked decrease in acylcarnitines in senescent human pancreatic carcinoma PANC-1 cells, indicating low CPT1C activity. Direct analyses of mRNA and protein show that CPT1C is significantly reduced in senescent cells. Furthermore, abnormal mitochondrial function was observed in senescent PANC-1 cells, leading to lower cell survival under metabolic stress and suppressed tumorigenesis in a mouse xenograft model. Knock-down of CPT1C in PANC-1 cells induced mitochondrial dysfunction, caused senescence-like growth suppression and cellular senescence, suppressed cell survival under metabolic stress, and inhibited tumorigenesis in vivo. Further, CPT1C knock-down suppressed xenograft tumor growth in situ. Silencing of CPT1C in five other tumor cell lines also caused cellular senescence. On the contrary, gain-of-function of CPT1C reversed PANC-1 cell senescence and enhanced mitochondrial function. This study identifies CPT1C as a novel biomarker and key regulator of cancer cell senescence through mitochondria-associated metabolic reprograming, and suggests that inhibition of CPT1C may represent a new therapeutic strategy for cancer treatment through induction of tumor senescence.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1-14 |
| Number of pages | 14 |
| Journal | Cell Death and Differentiation |
| DOIs | |
| State | Accepted/In press - Jan 9 2018 |
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ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
Cite this
Carnitine palmitoyltransferase 1C regulates cancer cell senescence through mitochondria-associated metabolic reprograming. / Wang, Yongtao; Chen, Yixin; Guan, Lihuan; Zhang, Huizheng; Huang, Yaoyao; Johnson, Caroline H.; Wu, Zeming; Gonzalez, Frank J.; Yu, Aiming; Huang, Peng; Wang, Ying; Yang, Shouhui; Chen, Pan; Fan, Xiaomei; Huang, Min; Bi, Huichang.
In: Cell Death and Differentiation, 09.01.2018, p. 1-14.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Carnitine palmitoyltransferase 1C regulates cancer cell senescence through mitochondria-associated metabolic reprograming
AU - Wang, Yongtao
AU - Chen, Yixin
AU - Guan, Lihuan
AU - Zhang, Huizheng
AU - Huang, Yaoyao
AU - Johnson, Caroline H.
AU - Wu, Zeming
AU - Gonzalez, Frank J.
AU - Yu, Aiming
AU - Huang, Peng
AU - Wang, Ying
AU - Yang, Shouhui
AU - Chen, Pan
AU - Fan, Xiaomei
AU - Huang, Min
AU - Bi, Huichang
PY - 2018/1/9
Y1 - 2018/1/9
N2 - Cellular senescence is a fundamental biological process that has profound implications in cancer development and therapeutics, but the underlying mechanisms remain elusive. Here we show that carnitine palmitoyltransferase 1C (CPT1C), an enzyme that catalyzes carnitinylation of fatty acids for transport into mitochondria for β-oxidation, plays a major role in the regulation of cancer cell senescence through mitochondria-associated metabolic reprograming. Metabolomics analysis suggested alterations in mitochondria activity, as revealed by the marked decrease in acylcarnitines in senescent human pancreatic carcinoma PANC-1 cells, indicating low CPT1C activity. Direct analyses of mRNA and protein show that CPT1C is significantly reduced in senescent cells. Furthermore, abnormal mitochondrial function was observed in senescent PANC-1 cells, leading to lower cell survival under metabolic stress and suppressed tumorigenesis in a mouse xenograft model. Knock-down of CPT1C in PANC-1 cells induced mitochondrial dysfunction, caused senescence-like growth suppression and cellular senescence, suppressed cell survival under metabolic stress, and inhibited tumorigenesis in vivo. Further, CPT1C knock-down suppressed xenograft tumor growth in situ. Silencing of CPT1C in five other tumor cell lines also caused cellular senescence. On the contrary, gain-of-function of CPT1C reversed PANC-1 cell senescence and enhanced mitochondrial function. This study identifies CPT1C as a novel biomarker and key regulator of cancer cell senescence through mitochondria-associated metabolic reprograming, and suggests that inhibition of CPT1C may represent a new therapeutic strategy for cancer treatment through induction of tumor senescence.
AB - Cellular senescence is a fundamental biological process that has profound implications in cancer development and therapeutics, but the underlying mechanisms remain elusive. Here we show that carnitine palmitoyltransferase 1C (CPT1C), an enzyme that catalyzes carnitinylation of fatty acids for transport into mitochondria for β-oxidation, plays a major role in the regulation of cancer cell senescence through mitochondria-associated metabolic reprograming. Metabolomics analysis suggested alterations in mitochondria activity, as revealed by the marked decrease in acylcarnitines in senescent human pancreatic carcinoma PANC-1 cells, indicating low CPT1C activity. Direct analyses of mRNA and protein show that CPT1C is significantly reduced in senescent cells. Furthermore, abnormal mitochondrial function was observed in senescent PANC-1 cells, leading to lower cell survival under metabolic stress and suppressed tumorigenesis in a mouse xenograft model. Knock-down of CPT1C in PANC-1 cells induced mitochondrial dysfunction, caused senescence-like growth suppression and cellular senescence, suppressed cell survival under metabolic stress, and inhibited tumorigenesis in vivo. Further, CPT1C knock-down suppressed xenograft tumor growth in situ. Silencing of CPT1C in five other tumor cell lines also caused cellular senescence. On the contrary, gain-of-function of CPT1C reversed PANC-1 cell senescence and enhanced mitochondrial function. This study identifies CPT1C as a novel biomarker and key regulator of cancer cell senescence through mitochondria-associated metabolic reprograming, and suggests that inhibition of CPT1C may represent a new therapeutic strategy for cancer treatment through induction of tumor senescence.
UR - http://www.scopus.com/inward/record.url?scp=85040233941&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85040233941&partnerID=8YFLogxK
U2 - 10.1038/s41418-017-0013-3
DO - 10.1038/s41418-017-0013-3
M3 - Article
C2 - 29317762
AN - SCOPUS:85040233941
SP - 1
EP - 14
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
ER -