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Phosphoglycerate dehydrogenase is dispensable for breast tumor maintenance and growth.

Chen J, Chung F, Yang G, Pu M, Gao H, Jiang W, Yin H, Capka V, Kasibhatla S, Laffitte B, Jaeger S, Pagliarini R, Chen Y, Zhou W - Oncotarget (2013)

Bottom Line: Cancer cells rely on aerobic glycolysis to maintain cell growth and proliferation via the Warburg effect.PHGDH knockdown in these cells leads to a reduction of serine synthesis and impairment of cancer cell proliferation.However, PHGDH knockdown does not affect tumor maintenance and growth in established breast cancer xenograft models, suggesting that PHGDH-dependent cancer cell growth may be context-dependent.

View Article: PubMed Central - PubMed

Affiliation: Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States.

ABSTRACT
Cancer cells rely on aerobic glycolysis to maintain cell growth and proliferation via the Warburg effect. Phosphoglycerate dehydrogenase (PHDGH) catalyzes the first step of the serine biosynthetic pathway downstream of glycolysis, which is a metabolic gatekeeper both for macromolecular biosynthesis and serine-dependent DNA synthesis. Here, we report that PHDGH is overexpressed in many ER-negative human breast cancer cell lines. PHGDH knockdown in these cells leads to a reduction of serine synthesis and impairment of cancer cell proliferation. However, PHGDH knockdown does not affect tumor maintenance and growth in established breast cancer xenograft models, suggesting that PHGDH-dependent cancer cell growth may be context-dependent. Our findings suggest that other mechanisms or pathways may bypass exclusive dependence on PHGDH in established human breast cancer xenografts, indicating that PHGDH is dispensable for the growth and maintenance and of tumors in vivo.

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PHGDH knockdown does not affect tumor growth in xenograft mouse models
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Figure 4: PHGDH knockdown does not affect tumor growth in xenograft mouse models

Mentions: To further understand the role of PHGDH in tumor growth and maintenance in vivo, nude mice were injected subcutaneously with MDA-MB-468, HCC1806 or BT-20 cells expressing Doxycycline-inducible shRNA to PHGDH. In the MDA-MB-468 xenograft mouse model, one PHGDH shRNA showed some growth effects, but this didn't correlate with PHGDH knockdown, raising the concern that the growth effect observed was due to off target of this hairpin in the 468 cell line (Fig. 4A and B). The other PHGDH shRNA did not inhibit tumor growth significantly (Fig. 4A), although robust PHGDH knockdown was achieved (Fig. 4B). Similar to the MDA-MB-468 xenograft mouse model, PHGDH shRNA also did not inhibit tumor growth significantly in HCC1806 and BT-20 xenograft mouse models (Fig. 4C and E), although robust PHGDH knockdown was also achieved in either the mRNA or protein level (Fig. 4D and F). These results demonstrate that, although a dependence of breast cancer cell proliferation on PHGDH activity was found in vitro, PHGDH is not required for breast tumor maintenance and growth in vivo.


Phosphoglycerate dehydrogenase is dispensable for breast tumor maintenance and growth.

Chen J, Chung F, Yang G, Pu M, Gao H, Jiang W, Yin H, Capka V, Kasibhatla S, Laffitte B, Jaeger S, Pagliarini R, Chen Y, Zhou W - Oncotarget (2013)

PHGDH knockdown does not affect tumor growth in xenograft mouse models
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926844&req=5

Figure 4: PHGDH knockdown does not affect tumor growth in xenograft mouse models
Mentions: To further understand the role of PHGDH in tumor growth and maintenance in vivo, nude mice were injected subcutaneously with MDA-MB-468, HCC1806 or BT-20 cells expressing Doxycycline-inducible shRNA to PHGDH. In the MDA-MB-468 xenograft mouse model, one PHGDH shRNA showed some growth effects, but this didn't correlate with PHGDH knockdown, raising the concern that the growth effect observed was due to off target of this hairpin in the 468 cell line (Fig. 4A and B). The other PHGDH shRNA did not inhibit tumor growth significantly (Fig. 4A), although robust PHGDH knockdown was achieved (Fig. 4B). Similar to the MDA-MB-468 xenograft mouse model, PHGDH shRNA also did not inhibit tumor growth significantly in HCC1806 and BT-20 xenograft mouse models (Fig. 4C and E), although robust PHGDH knockdown was also achieved in either the mRNA or protein level (Fig. 4D and F). These results demonstrate that, although a dependence of breast cancer cell proliferation on PHGDH activity was found in vitro, PHGDH is not required for breast tumor maintenance and growth in vivo.

Bottom Line: Cancer cells rely on aerobic glycolysis to maintain cell growth and proliferation via the Warburg effect.PHGDH knockdown in these cells leads to a reduction of serine synthesis and impairment of cancer cell proliferation.However, PHGDH knockdown does not affect tumor maintenance and growth in established breast cancer xenograft models, suggesting that PHGDH-dependent cancer cell growth may be context-dependent.

View Article: PubMed Central - PubMed

Affiliation: Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States.

ABSTRACT
Cancer cells rely on aerobic glycolysis to maintain cell growth and proliferation via the Warburg effect. Phosphoglycerate dehydrogenase (PHDGH) catalyzes the first step of the serine biosynthetic pathway downstream of glycolysis, which is a metabolic gatekeeper both for macromolecular biosynthesis and serine-dependent DNA synthesis. Here, we report that PHDGH is overexpressed in many ER-negative human breast cancer cell lines. PHGDH knockdown in these cells leads to a reduction of serine synthesis and impairment of cancer cell proliferation. However, PHGDH knockdown does not affect tumor maintenance and growth in established breast cancer xenograft models, suggesting that PHGDH-dependent cancer cell growth may be context-dependent. Our findings suggest that other mechanisms or pathways may bypass exclusive dependence on PHGDH in established human breast cancer xenografts, indicating that PHGDH is dispensable for the growth and maintenance and of tumors in vivo.

Show MeSH
Related in: MedlinePlus