The PI3K/Akt Pathway and Glucose Metabolism: A Dangerous Liaison in Cancer

Abstract

Aberrant activation of the PI3K/Akt pathway commonly occurs in cancers and correlates with multiple aspects of malignant progression. In particular, recent evidence suggests that the PI3K/Akt signaling plays a fundamental role in promoting the so-called aerobic glycolysis or Warburg effect, by phosphorylating different nutrient transporters and metabolic enzymes, such as GLUT1, HK2, PFKB3/4 and PKM2, and by regulating various molecular networks and proteins, including mTORC1, GSK3, FOXO transcription factors, MYC and HIF-1α. This leads to a profound reprogramming of cancer metabolism, also impacting on pentose phosphate pathway, mitochondrial oxidative phosphorylation, de novo lipid synthesis and redox homeostasis and thereby allowing the fulfillment of both the catabolic and anabolic demands of tumor cells. The present review discusses the interactions between the PI3K/Akt cascade and its metabolic targets, focusing on their possible therapeutic implications.

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124. 124.

     Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Natl Acad Sci [Internet]. 2011;108:4129-34.

     Not in our library10.1073/pnas.1014769108

125. 125.
     The updated landscape of tumor microenvironment and drug repurposing · 2020

     No notice
126. 126.

     Interaction between adipose tissue and cancer cells: role for cancer progression. Cancer Metastasis Rev [Internet]. 2021;40:31-46.

     Not in our library10.1007/s10555-020-09934-2

127. 127.

     Adipocyte-Derived Extracellular Vesicles Promote Prostate Cancer Cell Aggressiveness by Enabling Multiple Phenotypic and Metabolic Changes. Cells [Internet]. 2022;11:2388.

     Not in our library10.3390/cells11152388

128. 128.

     Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1α activation. Oncotarget [Internet]. 2016;7:64854-77.

     Not in our library10.18632/oncotarget.11712

129. 129.

     Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell Proliferation. Annu Rev Cell Dev Biol [Internet]. 2011;27:441-64.

     Not in our library10.1146/annurev-cellbio-092910-154237

130. 130.
     Regulation of mammalian nucleotide metabolism and biosynthesis · 2015

     No notice
131. 131.
     Cancer Cells Tune the Signaling Pathways to Empower de Novo Synthesis of Nucleotides · 2019

     No notice
132. 132.

     The pentose phosphate pathway in health and disease. Nat Metab [Internet]. 2023;5:1275-89.

     Not in our library10.1038/s42255-023-00863-2

133. 133.

     Deoxyribonucleotide Triphosphate Metabolism in Cancer and Metabolic Disease. Front Endocrinol (Lausanne) [Internet]. 2018; 9. Available at: http://journal.frontiersin.org/article/10.3389/fendo. 2018.

     Not in our library10.3389/fendo.2018.00177

134. 134.

     Akt Phosphorylation and Regulation of Transketolase Is a Nodal Point for Amino Acid Control of Purine Synthesis. Mol Cell [Internet]. 2014;55:264-76.

     Not in our library10.1016/j.molcel.2014.05.028

135. 135.

     Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion. Proc Natl Acad Sci [Internet]. 2016.

     Not in our library10.1073/pnas.1522223113

136. 136.

     Direct role of nucleotide metabolism in C-MYC-dependent proliferation of melanoma cells. Cell Cycle [Internet]. 2008;7:2392-400.

     Not in our library10.4161/cc.6390

137. 137.

     Protein and Nucleotide Biosynthesis Are Coupled by a Single Rate-Limiting Enzyme, PRPS2, to Drive Cancer. Cell [Internet]. 2014;157:1088-103.

     Not in our library10.1016/j.cell.2014.03.052

138. 138.

     6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 and 4: A pair of valves for fine-tuning of glucose metabolism in human cancer. Mol Metab [Internet]. 2019;20:1-13.

     Not in our library10.1016/j.molmet.2018.11.013

139. 139.

     Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell [Internet]. 2006;9:425-34.

     Not in our library10.1016/j.ccr.2006.04.023

140. 140.

     Respiratory competent mitochondria in human ovarian and peritoneal cancer. Mitochondrion [Internet]. 2011;11:437-43.

     Not in our library10.1016/j.mito.2010.12.015

141. 141.

     Comparative Metabolic Flux Profiling of Melanoma Cell Lines. J Biol Chem [Internet]. 2011;286:42626-34.

     Not in our library10.1074/jbc.m111.282046

142. 142.

     Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer [Internet]. 2011;11:325-37.

     Not in our library10.1038/nrc3038

143. 143.

     The PI3K/Akt Pathway Regulates Oxygen Metabolism via Pyruvate Dehydrogenase (PDH)-E1α Phosphorylation. Mol Cancer Ther [Internet]. 2015;14:1928-38.

     Not in our library10.1158/1535-7163.mct-14-0888

144. 144.

     The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer [Internet]. 2016;16:732-49.

     Not in our library10.1038/nrc.2016.89

145. 145.

     PTEN/Akt Signaling Controls Mitochondrial Respiratory Capacity through 4E-BP1. Koritzinsky M, Ed. PLoS One [Internet]. 2012;7:e45806.

     Not in our library10.1371/journal.pone.0045806

146. 146.

     The multifaceted roles of mitochondria at the crossroads of cell life and death in cancer. Free Radic Biol Med [Internet]. 2021;176:203-21.

     Not in our library10.1016/j.freeradbiomed.2021.09.024

147. 147.

     Unraveling the Peculiar Features of Mitochondrial Metabolism and Dynamics in Prostate Cancer. Cancers (Basel) [Internet]. 2023;15:1192.

     Not in our library10.3390/cancers15041192

148. 148.

     Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review). Oncol Lett [Internet]. 2012;4:1151-7.

     Not in our library10.3892/ol.2012.928

149. 149.

     'Reverse Warburg effect' of cancer-associated fibroblasts (Review). Int J Oncol [Internet]. 2022;60:67.

     Not in our library10.3892/ijo.2022.5357

150. 150.
     Metabolic reprogramming of cancer-associated fibroblasts and its effect on cancer cell reprogramming · 2021

     No notice
151. 151.

     Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer [Internet]. 2013;13:227-32.

     Not in our library10.1038/nrc3483

152. 152.

     Substrate channeling in the glycerol-3-phosphate pathway regulates the synthesis, storage and secretion of glycerolipids. Biochim Biophys Acta - Mol Cell Biol Lipids [Internet]. 2020;1865:158438.

     Not in our library10.1016/j.bbalip.2019.03.010

153. 153.

     Akt-Dependent Metabolic Reprogramming Regulates Tumor Cell Histone Acetylation. Cell Metab [Internet]. 2014;20:306-19.

     Not in our library10.1016/j.cmet.2014.06.004

154. 154.

     Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis. Cancer Discov [Internet]. 2019;9:416-35.

     Not in our library10.1158/2159-8290.cd-18-0567

155. 155.

     ATP Citrate Lyase (ACLY): A Promising Target for Cancer Prevention and Treatment. Curr Drug Targets [Internet]. 2015;16:156-63.

     Not in our library10.2174/1389450115666141224125117

156. 156.

     ATP citrate lyase (ACLY) inhibitors: An anti-cancer strategy at the crossroads of glucose and lipid metabolism. Eur J Med Chem [Internet]. 2018;157:1276-91.

     Not in our library10.1016/j.ejmech.2018.09.001

157. 157.

     PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene [Internet]. 2005;24:6465-81.

     Not in our library10.1038/sj.onc.1208802

158. 158.

     Role of the Sterol Regulatory Element Binding Protein Pathway in Tumorigenesis. Front Oncol [Internet]. 2020; 10. Available at: https://www.frontiersin.org/article/10.3389/fonc. 2020.

     Not in our library10.3389/fonc.2020.01788

159. 159.

     Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP. Oncogene [Internet]. 2016;35:1250-60.

     Not in our library10.1038/onc.2015.179

160. 160.

     Regulatory Role of Glycogen Synthase Kinase 3 for Transcriptional Activity of ADD1/SREBP1c. J Biol Chem [Internet]. 2004;279:51999-2006.

     Not in our library10.1074/jbc.m405522200

161. 161.

     The MYC Oncogene Cooperates with Sterol-Regulated Element-Binding Protein to Regulate Lipogenesis Essential for Neoplastic Growth. Cell Metab [Internet]. 2019;30:556-572.e5.

     Not in our library10.1016/j.cmet.2019.07.012

162. 162.

     Targeting SREBP-1-driven Lipid Metabolism to Treat Cancer. Curr Pharm Des [Internet]. 2014;20:2619-26.

     Not in our library10.2174/13816128113199990486

163. 163.

     Reactive oxygen species in cancer: Current findings and future directions. Cancer Sci [Internet]. 2021;112:3945-52.

     Not in our library10.1111/cas.15068

164. 164.
     Phosphoinositide 3-Kinase/Akt Signaling and Redox Metabolism in Cancer · 2018

     No notice
165. 165.

     PIK3CA mutant tumors depend on oxoglutarate dehydrogenase. Proc Natl Acad Sci [Internet]. 2017.

     Not in our library10.1073/pnas.1617922114

166. 166.

     Direct stimulation of NADP + synthesis through Akt-mediated phosphorylation of NAD kinase. Science (80- ) [Internet]. 2019;363:1088-92.

     Not in our library10.1126/science.aau3903

167. 167.

     NRF2 in Cancer: Cross-Talk with Oncogenic Pathways and Involvement in Gammaherpesvirus-Driven Carcinogenesis. Int J Mol Sci [Internet]. 2022;24:595.

     Not in our library10.3390/ijms24010595

168. 168.

     Mitochondrial functional and structural impairment is involved in the antitumor activity of δ-tocotrienol in prostate cancer cells. Free Radic Biol Med [Internet]. 2020.

     Not in our library10.1016/j.freeradbiomed.2020.07.009

169. 169.

     Oxidative stress downstream of mTORC1 but not AKT causes a proliferative defect in cancer cells resistant to PI3K inhibition. Oncogene [Internet]. 2017;36:2762-74.

     Not in our library10.1038/onc.2016.435

170. 170.
     ROS in cancer therapy: the bright side of the moon · 2020

     No notice
171. 171.
     PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects · 2021

     No notice
172. 172.

     Clinical Development of AKT Inhibitors and Associated Predictive Biomarkers to Guide Patient Treatment in Cancer Medicine. Pharmgenomics Pers Med [Internet]. 2021.

     Not in our library10.2147/pgpm.s305068

Cited by papers we hold 1

• Mitochondrial metabolism and cancer therapeutic innovation · 2025
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