Definition of a Novel Feed-Forward Mechanism for Glycolysis-HIF1α Signaling in Hypoxic Tumors Highlights Aldolase A as a Therapeutic Target.
The hypoxia-inducible transcription factor HIF1α drives expression of many glycolytic enzymes. Here, we show that hypoxic glycolysis, in turn, increases HIF1α transcriptional activity and stimulates tumor growth, revealing a novel feed-forward mechanism of glycolysis-HIF1α signaling. Negative regulation of HIF1α by AMPK1 is bypassed in hypoxic cells, due to ATP elevation by increased glycolysis, thereby preventing phosphorylation and inactivation of the HIF1α transcriptional coactivator p300. Notably, of the HIF1α-activated glycolytic enzymes we evaluated by gene silencing, aldolase A (ALDOA) blockade produced the most robust decrease in glycolysis, HIF-1 activity, and cancer cell proliferation. Furthermore, either RNAi-mediated silencing of ALDOA or systemic treatment with a specific small-molecule inhibitor of aldolase A was sufficient to increase overall survival in a xenograft model of metastatic breast cancer. In establishing a novel glycolysis-HIF-1α feed-forward mechanism in hypoxic tumor cells, our results also provide a preclinical rationale to develop aldolase A inhibitors as a generalized strategy to treat intractable hypoxic cancer cells found widely in most solid tumors. Cancer Res; 76(14); 4259-69. ©2016 AACR.
Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center. Houston, TX.|Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
Geoffrey
G
Grandjean
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
Petrus R
PR
de Jong
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
Brian
B
James
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
Mei Yee
MY
Koh
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
Robert
R
Lemos
Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center. Houston, TX.
John
J
Kingston
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
Alexander
A
Aleshin
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
Laurie A
LA
Bankston
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
Claudia P
CP
Miller
Department of Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, TX.
Eun Jeong
EJ
Cho
Department of Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, TX.
Ramakrishna
R
Edupuganti
Department of Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, TX.
Ashwini
A
Devkota
Department of Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, TX.
Gabriel
G
Stancu
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
Robert C
RC
Liddington
Department of Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, TX.
Kevin
K
Dalby
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
Garth
G
Powis
D055372:AMP-Activated Protein Kinases / Q000502:physiology; D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000502:physiology; D005634:Fructose-Bisphosphate Aldolase / Q000037:antagonists & inhibitors*; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D055372:AMP-Activated Protein Kinases; D005634:Fructose-Bisphosphate Aldolase