RETRACTED ARTICLE: Decreased Warburg effect induced by ATP citrate lyase suppression inhibits tumor growth in pancreatic cancer

Pancreatic cancer (PC) ranks twelfth in frequency of diagnosis but is the fourth leading cause of cancer related deaths with a 5 year survival rate of less than 7 percent. This poor prognosis occurs because the early stages of PC are often asymptomatic. Over-expression of several growth factors, most notably vascular endothelial growth factor (VEGF), has been implicated in PC resulting in dysfunctional signal transduction pathways and the facilitation of tumor growth, invasion and metastasis. Hepatocyte growth factor (HGF) acts via the Met receptor and has also received research attention with ongoing efforts to develop treatments to block the Met receptor and its signal transduction pathways. Macrophage-stimulating protein (MSP), and its receptor Ron, is also recognized as important in the etiology of PC but is less well studied. Although the angiotensin II (AngII)/AT1 receptor system is best known for mediating blood pressure and body water/electrolyte balance, it also facilitates tumor vascularization and growth by stimulating the expression of VEGF. A metabolite of AngII, angiotensin IV (AngIV) has sequence homology with the “hinge regions” of HGF and MSP, key structures in the growth factor dimerization processes necessary for Met and Ron receptor activation. We have developed AngIV-based analogs designed to block dimerization of HGF and MSP and thus receptor activation. Norleual has shown promise as tested utilizing PC cell cultures. Results indicate that cell migration, invasion, and pro-survival functions were suppressed by this analog and tumor growth was significantly inhibited in an orthotopic PC mouse model.

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Type Iγ phosphatidylinositol phosphate kinase promotes tumor growth by facilitating Warburg effect in colorectal cancer

EBioMedicine ◽

10.1016/j.ebiom.2019.05.015 ◽

2019 ◽

Vol 44 ◽

pp. 375-386 ◽

Cited By ~ 6

Author(s):

Wei Peng ◽

Wei Huang ◽

Xiaoxiao Ge ◽

Liqiong Xue ◽

Wei Zhao ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Growth ◽

Warburg Effect ◽

Phosphatidylinositol Phosphate ◽

Phosphatidylinositol Phosphate Kinase

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Acetyl-CoA is produced by the citrate synthase homology module of ATP-citrate lyase

Nature Structural & Molecular Biology ◽

10.1038/s41594-021-00624-3 ◽

2021 ◽

Author(s):

Kenneth Verstraete ◽

Koen H. G. Verschueren ◽

Ann Dansercoer ◽

Savvas N. Savvides

Keyword(s):

Citrate Synthase ◽

Atp Citrate Lyase ◽

Acetyl Coa ◽

Citrate Lyase ◽

Homology Module

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IGF1-mediated HOXA13 overexpression promotes colorectal cancer metastasis through upregulating ACLY and IGF1R

Cell Death and Disease ◽

10.1038/s41419-021-03833-2 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Chenyang Qiao ◽

Wenjie Huang ◽

Jie Chen ◽

Weibo Feng ◽

Tongyue Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Growth Factor ◽

Cancer Metastasis ◽

Combined Treatment ◽

Insulin Like Growth Factor ◽

Atp Citrate Lyase ◽

Citrate Lyase ◽

Elevated Expression ◽

Igf1r Inhibitor ◽

Colorectal Cancer Metastasis

AbstractMetastasis is the major reason for the high mortality of colorectal cancer (CRC) patients and its molecular mechanism remains unclear. Here, we report a novel role of Homeobox A13 (HOXA13), a member of the Homeobox (HOX) family, in promoting CRC metastasis. The elevated expression of HOXA13 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in two independent CRC cohorts. Overexpression of HOXA13 promoted CRC metastasis whereas downregulation of HOXA13 suppressed CRC metastasis. Mechanistically, HOXA13 facilitated CRC metastasis by transactivating ATP-citrate lyase (ACLY) and insulin-like growth factor 1 receptor (IGF1R). Knockdown of ACLY and IGFIR inhibited HOXA13-medicated CRC metastasis, whereas ectopic overexpression of ACLY and IGFIR rescued the decreased CRC metastasis induced by HOXA13 knockdown. Furthermore, Insulin-like growth factor 1 (IGF1), the ligand of IGF1R, upregulated HOXA13 expression through the PI3K/AKT/HIF1α pathway. Knockdown of HOXA13 decreased IGF1-mediated CRC metastasis. In addition, the combined treatment of ACLY inhibitor ETC-1002 and IGF1R inhibitor Linsitinib dramatically suppressed HOXA13-mediated CRC metastasis. In conclusion, HOXA13 is a prognostic biomarker in CRC patients. Targeting the IGF1-HOXA13-IGF1R positive feedback loop may provide a potential therapeutic strategy for the treatment of HOXA13-driven CRC metastasis.

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