Growth Promoting Metabolic Alterations

Slide 1 · Growth-Promoting Metabolic Alterations

Cancer growth depends on rerouting nutrient carbon toward new cell material.

Metabolic reprogramming links oncogenic signaling to biosynthesis.

The Warburg effect is a prominent, but not cancer-specific, example.

Glucose, glutamine, mitochondria, and tumor suppressors act as one system.

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Define aerobic glycolysis and explain why oxygen does not suppress it in growing cells.

Contrast ATP production with the need for biosynthetic carbon intermediates.

Trace how RTK–PI3K–AKT, MYC, STK11 and p53 reshape metabolism.

Interpret FDG-PET avidity and inherited Krebs-cycle tumor-suppressor defects.

Slide 3 · Metabolism becomes a growth program

Growth-related signals

Changed nutrient handling

Biosynthetic intermediates

Cellular mass for division

Molecular basis of cancer: An altered cellular phenotype

Malignant cells exploit a metabolic program also used by rapidly growing normal tissues.

Mutations favor sustained activation of a program normally linked to controlled growth.

Slide 4 · Warburg effect: The defining phenotype

High glucose uptake and glycolytic fermentation despite available oxygen.

The presence of oxygen does not necessarily shift the cell to maximal glucose oxidation.

Cancer cells often convert substantial glucose-derived carbon to lactate.

This pattern is called aerobic glycolysis.

Slide 5 · Aerobic glycolysis is not oxygen deprivation

Aerobic glycolysis

Oxygen is available to the cell.

Glucose is avidly taken up.

Fermentative glycolysis remains prominent.

True oxygen limitation

Insufficient oxygen constrains respiratory metabolism.

Glycolysis can sustain some ATP production.

Do not equate these distinct causes of lactate production.

The word “aerobic” describes oxygen availability, not exclusive mitochondrial respiration.

Slide 6 · What happens to incoming glucose?

Glucose enters cell

Glycolytic intermediates

Pyruvate formation

Substantial lactate output

Simplified carbon-fate schematic

Rapid glucose uptake can accompany growth even in oxygen-rich conditions.

Some intermediates branch from the pathway to support anabolism.

Slide 7 · Increased glucose uptake has a purpose

Growth demands a sustained supply of intracellular carbon molecules.

Glycolysis provides both usable energy and intermediate compounds.

Transport and enzyme activity are increased by progrowth signaling.

Glucose avidity is a metabolic behavior—not a stand-alone cancer diagnosis.

Slide 8 · The Warburg effect is not cancer-specific

Growing normal cells

Embryonic and other proliferating tissues can adopt aerobic glycolysis.

Growth signals normally regulate the transition.

Biosynthetic needs drive the pattern.

Cancer cells

Similar anabolic metabolism is often sustained.

Oncogenic mutations deregulate its control.

The phenotype is common, not exclusive to malignancy.

Slide 9 · Cell division imposes a mass-balance requirement

One proliferating cell

Make DNA, RNA and proteins

Make lipids and organelles

Two daughter cells

Before one cell becomes two, its contents must be duplicated

A cell cannot divide successfully by generating ATP alone.

Biosynthesis requires retaining and redirecting nutrient carbon.

Slide 10 · Energy production versus precursor generation

Catabolic emphasis

Oxidize fuel to harvest energy.

Complete glucose oxidation releases carbon as CO₂.

Efficient ATP output does not itself build biomass.

Anabolic emphasis

Preserve carbon in useful intermediate pools.

Route carbon into nucleic acids, proteins and lipids.

Supply molecular components for cell growth.

Proliferation requires energy AND substrates for macromolecules.

Slide 11 · Two contrasting fates of glucose carbon

Feature

Complete oxidation

Growth-directed metabolism

Primary emphasis

Energy generation

Energy plus biomass precursors

Carbon fate

Much is ultimately lost as CO₂

A fraction is retained in intermediates

Growth utility

Supports ATP requirements

Supports macromolecule production

Key point

Not sufficient alone for division

Compatible with rapid proliferation

Slide 12 · Why complete oxidation loses usable carbon

Glucose + oxygen

Mitochondrial oxidation

Carbon dioxide + water

ATP generated

Simplified net reaction highlighted

Complete oxidation extracts energy but releases glucose-derived carbon as CO₂.

Those carbon atoms can no longer be incorporated into cellular building blocks.

Slide 13 · Diversion points support biosynthesis

Glycolytic carbon intermediates

Nucleotide precursors

Protein-associated precursors

Other biosynthetic substrates

New cell material

The advantage is access to molecular precursors, not maximal ATP per glucose.

Slide 14 · Nucleic acids require new carbon

Cell replication requires additional DNA and RNA.

Carbon intermediates derived from central metabolism support nucleotide synthesis.

Diverting intermediates away from complete oxidation helps meet this demand.

The textbook links these needs to glycolytic precursor pools.

Slide 15 · DNA/RNA synthesis is part of the growth logic

High glucose availability

Metabolic intermediates

Nucleotide synthesis

Genome and RNA duplication

Conceptual link; Not a detailed biochemical pathway

A proliferating cell requires chemical precursors as well as replication machinery.

The metabolic phenotype helps sustain this biosynthetic burden.

Slide 16 · Protein synthesis creates another demand

Expanding cell mass requires synthesis of many proteins.

Growth signals coordinate metabolic substrate availability with protein production.

Carbon is retained in cellular constituents rather than converted exclusively to CO₂.

PI3K/AKT signaling also stimulates factors required for protein synthesis.

Slide 17 · Lipids are needed for membrane expansion

Mitochondrial citrate

Acetyl-CoA supply

Lipid biosynthesis

Membrane expansion

Citrate links mitochondrial metabolism to cytoplasmic lipid biosynthesis

Acetyl-CoA is essential for lipid synthesis.

Citrate generated in mitochondria as a major upstream source.

Slide 18 · Organelle duplication is a metabolic task

Division entails reproduction of cellular structures, not just chromosomal DNA.

Organelle growth consumes proteins, lipids, and other macromolecules.

A growth-supporting metabolic network must provide multiple precursor classes.

The resulting demand explains why metabolism is integrated with proliferation.

Slide 19 · What must a growing cell manufacture?

Cellular component

Biosynthetic demand

Metabolic implication

DNA and RNA

New nucleic acids

Reserve suitable carbon intermediates

Proteins

Expanded protein mass

Coordinate precursors and synthesis machinery

Lipids

New membrane material

Supply citrate-derived acetyl-CoA

Organelles

Cellular structural material

Coordinate multiple synthetic pathways

Slide 20 · ATP efficiency is not the only optimum

The best metabolic state for division need not maximize ATP per glucose molecule.

Aerobic glycolysis appears energetically inefficient in isolation.

Its intermediate pools provide substrate for biosynthetic pathways.

Tumor growth selects for an appropriate balance of energy and carbon supply.

Slide 21 · How ATP yields

Pathway scenario

Textbook value

Interpretation

“Pure” glycolysis

2 ATP / glucose

Limited ATP, useful metabolite intermediates

Complete oxidative phosphorylation

36 ATP / glucose

Historical textbook comparison

Growth-associated mixed metabolism

~4 ATP / glucose (average)

Represents mixed glycolytic/oxidative flux

Illustrative textbook values are not universal fixed cellular yields.

Slide 22 · The metabolic “sweet spot”

Why glycolysis stays prominent

Supports access to biosynthetic intermediates.

Maintains rapid uptake of glucose.

Provides some ATP directly.

Why respiration remains relevant

Growing cells still use mitochondria.

The Krebs cycle supplies biosynthetic precursors.

Mixed metabolism can better support mass production.

Slide 23 · Warburg metabolism does not abolish mitochondria

Growing cancer cells can be highly glycolytic and still depend on mitochondrial metabolism.

Mitochondria provide pathways for generating biosynthetic intermediates.

The Krebs cycle remains important even when fermentation is prominent.

A simple “glycolysis ON / mitochondria OFF” model is inaccurate.

Slide 24 · Quiescent and growing cells use carbon differently

Quiescent cell

Energy maintenance is a major priority.

The Krebs cycle supports ATP generation.

Macromolecules still require some precursor supply.

Growing cell

Glucose and glutamine uptake rise.

Intermediate production is redirected into anabolism.

Nucleotides, proteins and lipids are assembled.

Cellular state changes how metabolism is allocated.

Slide 25 · The Krebs cycle is a biosynthetic hub

Mitochondrial Krebs cycle

Intermediates for lipid synthesis

Other biosynthetic precursors

Support for ongoing mitochondrial reactions

Proliferative biomass

The text stresses carbon-intermediate generation as a major growth-related role.

Slide 26 · Citrate connects two metabolic compartments

Mitochondrial reactions

Citrate intermediate

Acetyl-CoA availability

Lipid production

A selected example from the Robbins mechanism

Citrate produced during mitochondrial metabolism supports lipid anabolism.

The diagram summarizes a functional connection, not every reaction in the pathway.

Slide 27 · Acetyl-CoA and lipid biogenesis

Acetyl coenzyme A supplies carbon used during lipid biosynthesis.

In growing cells, mitochondrial citrate is a major source upstream of acetyl-CoA.

The anabolic requirement helps explain mitochondrial activity during the Warburg state.

Metabolic carbon allocation connects growth signaling to membrane synthesis.

Slide 28 · Glutamine contributes carbon to mitochondrial metabolism

Glutamine uptake

Mitochondrial utilization

Krebs-cycle intermediates

Building-block synthesis

Substrate entry is shown conceptually

A large fraction of carbon entering mitochondrial pathways can derive from glutamine.

Growing cells therefore require glutamine uptake in addition to glucose uptake.

Slide 29 · Glucose and glutamine are complementary fuels

Glucose

Strongly increased uptake in many growing cells.

Supports glycolytic precursors.

Helps supply ATP and anabolic carbon.

Glutamine

Important entry source for mitochondrial metabolism.

Supports Krebs-cycle intermediate pools.

Used to furnish cellular building blocks.

Growth cannot be understood by considering glucose alone.

Slide 30 · A compartment-level account of growth metabolism

Location / process

Main role in this lecture

Important output

Glucose uptake

Increase substrate availability

Carbon enters cytoplasmic pathways

Glycolysis

Produce intermediates and some ATP

Precursors for biosynthesis

Mitochondrial Krebs cycle

Generate useful carbon intermediates

Citrate and other precursors

Biosynthetic pathways

Assemble cellular constituents

DNA, RNA, proteins, lipids

Slide 31 · Growth-factor signaling initiates reprogramming

Growth factor receptor

Intracellular signaling

Altered enzyme/transport activity

Biomass synthesis

Normal cells coordinate growth signals and metabolic output

Progrowth signaling links substrate availability to the decision to divide.

This response is regulated and transient in normal proliferating cells.

Slide 32 · Normal control versus oncogenic persistence

Physiologic control

Growth signals regulate metabolism.

Anabolic activity follows proliferation needs.

Regulatory pathways can restrain the state.

Cancer-associated deregulation

Oncogenes favor ongoing metabolic activation.

Loss of tumor-suppressor function weakens restraints.

Growth-promoting metabolism persists.

Slide 33 · Two opposing classes of regulatory genes

Metabolic control of growth

Oncogenic signaling → activation

Tumor suppressors → restraint

Enzyme-level substrate routing

Net growth phenotype

The Warburg phenotype emerges from integrated control, not one enzyme alone.

Slide 34 · RTK–PI3K–AKT is a metabolic switch

Receptor tyrosine kinase signaling

Phosphoinositide 3-kinase (PI3K)

AKT-dependent downstream actions

Increased glycolysis and anabolic support

This cascade coordinates transport, metabolic enzymes, lipid synthesis and protein synthesis.

Slide 35 · AKT signaling increases glucose transport

PI3K/AKT activation

Glucose-transporter activity

Higher glucose uptake

Greater glycolytic input

One major output of the pathway

Increased glucose-transporter activity downstream of PI3K/AKT.

A larger substrate supply supports carbon-intensive cell growth.

Slide 36 · AKT signaling stimulates glycolytic enzymes

PI3K/AKT activation

Glycolytic enzyme activity

Higher glycolytic flux

More available intermediates

Another major output of the pathway

Transporter changes and enzyme changes reinforce each other.

Increased pathway activity can feed energy generation and precursor production.

Slide 37 · AKT favors lipid-directed mitochondrial carbon

PI3K/AKT signaling

Mitochondrial intermediates

Anabolic diversion

Lipid biosynthesis

Metabolic routing is coupled to growth signaling

Mitochondrial products can be redirected toward lipids rather than fully oxidized.

This coupling supplies material for membrane expansion.

Slide 38 · AKT also supports protein production

PI3K/AKT signaling

Protein-synthesis factors

Increased protein synthesis

Growing cellular mass

Metabolic reprogramming extends beyond glycolysis

Protein synthesis is a coordinated output of progrowth signaling.

Nutrient capture alone would not produce a larger cell without synthetic machinery.

Slide 39 · PI3K/AKT acts at several metabolic levels

Level

Action described in Robbins

Growth consequence

Transport

Upregulates glucose transporters

More carbon substrate

Metabolism

Increases glycolytic enzymes

More glycolytic processing

Carbon allocation

Promotes diversion to lipid synthesis

Membrane building blocks

Synthesis machinery

Stimulates protein-synthesis factors

Greater protein production

Slide 40 · Pyruvate kinase normally completes glycolysis

Phosphoenolpyruvate

Pyruvate kinase

Pyruvate

Downstream carbon fate

Final glycolytic step highlighted in the source

Pyruvate kinase catalyzes conversion of phosphoenolpyruvate to pyruvate.

The textbook uses this step to illustrate how signaling redirects glycolytic intermediates.

Slide 41 · RTK signaling can inhibit pyruvate kinase

Receptor tyrosine kinase

PK phosphorylation

Lower PK activity

Reduced final-step throughput

Specific enzyme-level checkpoint

Phosphorylation-associated inhibition of pyruvate kinase.

This can restrain conversion of phosphoenolpyruvate into pyruvate.

Slide 42 · An upstream bottleneck creates a precursor pool

Upstream glycolytic intermediates

Carbon retained upstream

Diversion to nucleotide production

Diversion to protein-related synthesis

Increased anabolic supply

This is the “damming effect” described for pyruvate-kinase inhibition.

Slide 43 · Why slowing one reaction can favor cell growth

Without the bottleneck

The terminal step converts upstream substrate toward pyruvate.

Less accumulation occurs at that control point.

Flux distribution favors downstream passage.

With PK inhibition

Earlier metabolites accumulate.

A larger upstream pool can feed branch pathways.

The effect supports biosynthesis despite slower final-step flux.

Slide 44 · MYC coordinates an anabolic transcriptional program

MYC drives gene-expression changes that favor biosynthesis and cell growth.

Progrowth pathways upregulate the transcription factor MYC.

MYC increases expression of multiple glycolytic enzymes.

MYC also upregulates glutaminase, supporting glutamine use by mitochondria.

Slide 45 · MYC increases glycolytic capacity

Upregulated MYC

Glycolytic gene expression

Higher enzyme availability

Anabolic metabolic state

Gene regulation translates into metabolic activity

MYC contributes to the sustained glycolytic phenotype of growing cells.

Regulation occurs at the level of transcription as well as signal-induced enzyme activity.

Slide 46 · MYC increases glutaminase expression

MYC activation

Glutaminase upregulation

Mitochondrial glutamine use

Biosynthetic intermediates

The glutamine arm of metabolic growth

Glutaminase is needed for the mitochondrial utilization of glutamine described in the text.

The gene-expression program supports more than glucose metabolism.

Slide 47 · MYC unites two carbon-input programs

MYC transcriptional activity

Glycolytic enzymes

Glutaminase

Anabolic gene-expression program

Metabolites for growth

MYC connects nutrient handling with the cell’s increased synthetic burden.

Slide 48 · Tumor suppressors restrain anabolic metabolism

Growth arrest and metabolic restraint are closely intertwined.

Cancer-associated metabolic activation is not exclusively caused by oncogene gain.

Tumor suppressors oppose pathways that support glucose use and anabolism.

Loss of tumor-suppressor activity permits sustained growth-promoting metabolism.

Slide 49 · STK11/LKB1 acts as a metabolic regulator

STK11 kinase

Metabolic regulation

Restraint on growth-linked programs

Reduced uncontrolled proliferation

Established parent context on the same textbook page

STK11 affects glucose handling, protein synthesis, mitochondrial biology and lipids.

The source identifies its normal function as opposing Warburg-associated changes.

Slide 50 · STK11 has hereditary and somatic relevance

Germline STK11 loss

Causes Peutz–Jeghers syndrome.

Associated with gastrointestinal polyps.

Increases risk for multiple epithelial cancers.

Somatic STK11 loss

Occurs in diverse carcinomas.

Demonstrates that metabolic control can be altered during tumor evolution.

Links a tumor-suppressor defect to growth-supporting metabolism.

Slide 51 · P53 is a broad metabolic counterweight

Functional p53

Reduced glucose uptake/glycolysis

Reduced lipogenesis and NADPH

Less anabolic support

Several opposing effects

The metabolic targets are described collectively rather than as one isolated switch.

These inhibitory effects complement p53-mediated restraint of proliferation.

Slide 52 · Why NADPH matters for anabolism

NADPH is a cofactor needed in biosynthesis of macromolecules.

P53 represses processes contributing to NADPH generation.

Reducing reductive biosynthetic capacity can constrain cell growth.

NADPH control is one facet of the broader p53 metabolic program.

Slide 53 · Cancer gene products and metabolic direction

Regulator

Direction emphasized

Principal metabolic effect

PI3K/AKT

Promotes anabolic state

Glucose uptake, glycolysis, lipid/protein synthesis

MYC

Promotes anabolic state

Glycolytic enzymes and glutaminase

STK11

Opposes growth-linked state

Broad cellular metabolic restraint

p53

Opposes growth-linked state

Restricts glycolysis, lipids and NADPH

Slide 54 · Some Krebs-cycle enzymes are tumor suppressors

Loss of certain metabolic enzymes can predispose to neoplasia.

The source identifies fumarate hydratase (FH) and succinate dehydrogenase (SDH).

Germline loss-of-function mutations are associated with inherited tumor risks.

The mechanisms connecting impaired Krebs-cycle function to transformation are incompletely resolved.

Slide 55 · FH and SDH: Inherited neoplastic associations

FH (fumarate hydratase)

Encodes a Krebs-cycle enzyme.

Germline loss-of-function mutations predispose to tumors.

Renal cell carcinoma is among the associated tumor types noted.

SDH (succinate dehydrogenase)

Encodes a Krebs-cycle enzyme.

Inherited loss-of-function creates tumor susceptibility.

Pheochromocytoma is among the associated tumor types noted.

The examples are associations noted by Robbins—not an exhaustive syndrome classification.

Slide 56 · Why can impaired Krebs-cycle activity promote cancer?

Proposed mechanism 1

Krebs-cycle inhibition may favor a glycolytic growth phenotype.

Altered carbon routing could reinforce Warburg metabolism.

The source presents this as a hypothesis.

Proposed mechanism 2

Abnormal metabolites may exert oncogenic effects.

Such molecules are termed oncometabolites.

The detailed mechanisms belong to the adjacent oncometabolism topic.

The precise mechanism remains uncertain.

Slide 57 · FDG-PET exploits elevated glucose uptake

Injected ¹⁸F-FDG

Tumor and tissue uptake

PET detects tracer distribution

Regions of high uptake identified

Clinical translation of a common cancer metabolic phenotype

¹⁸F-fluorodeoxyglucose is a glucose analog used as a PET tracer.

The result reflects glucose avidity and is not uniquely specific for cancer.

Slide 58 · FDG accumulation is not restricted to tumors

Tumor-associated avidity

Many tumors are FDG-PET positive.

Rapidly growing tumors are often strongly avid.

Uptake is consistent with increased glucose handling.

Normal proliferating tissues

Active bone marrow may also take up tracer.

Normal tissue uptake can coexist with tumor uptake.

Interpretation needs appropriate clinical context.

Slide 59 · What FDG-PET can and cannot establish

Finding

Reasonable inference

Unwarranted inference

High FDG uptake

Increased glucose-avid activity

Definitive malignancy on metabolism alone

Tumor with strong avidity

A metabolic phenotype compatible with high growth

Specific oncogene mutation identified

Bone marrow tracer uptake

Normal actively dividing tissue may contribute

Every focus is a metastatic deposit

Slide 60 · Clinical application: A glucose-avid mass

A rapidly growing mass shows pronounced ¹⁸F-FDG uptake before the tissue diagnosis is established.

Question

Which metabolic property could explain the finding?

Reasoned interpretation

High glucose uptake is compatible with aerobic glycolysis. FDG avidity alone does not establish malignancy or histologic type.

Slide 61 · Mechanism application: A glycolytic bottleneck

A cancer cell receives strong receptor tyrosine kinase signaling that phosphorylates and inhibits pyruvate kinase.

Question

Why might precursor synthesis increase rather than decrease?

Reasoned interpretation

Reduced terminal glycolytic throughput permits upstream intermediates to accumulate and be diverted toward biosynthesis.

Slide 62 · Mechanism application: Loss of a Krebs-cycle enzyme

A hereditary loss-of-function mutation affects FH or SDH in a patient with increased tumor susceptibility.

Question

Can this be explained solely by reduced ATP generation?

Reasoned interpretation

No. The source suggests Warburg-type shifts and abnormal-metabolite effects; The precise oncogenic mechanism remains uncertain.

Slide 63 · Integrated mechanism: Substrate to proliferation

Control point

Metabolic consequence

Growth relevance

Glucose uptake

Larger substrate input

Supports anabolic precursor supply

Glycolytic regulation

Intermediates diverted

Nucleotides and other cell constituents

Glutamine use

Mitochondrial precursor supply

Supports multiple biosynthetic pathways

Oncogene/tumor-suppressor balance

Persistent anabolic program

Promotes uncontrolled cell growth

Slide 64 · Five examinable mechanistic conclusions

The Warburg effect is aerobic glycolysis—not proof of absent oxygen.

Its growth advantage lies in biosynthetic precursor production.

Mitochondria and glutamine remain central to proliferative metabolism.

PI3K/AKT and MYC promote, whereas STK11 and p53 oppose, this state.

¹⁸F-FDG uptake demonstrates glucose avidity, not cancer specificity.

Slide 65 · Four traps in interpreting metabolic reprogramming

A single metabolic observation rarely defines the whole cancer phenotype.

Aerobic glycolysis does not imply that mitochondria are nonfunctional.

High FDG uptake does not establish a diagnosis of malignancy.

Low ATP yield per glucose does not make a pathway disadvantageous for growth.

FH or SDH loss is associated with tumor risk, but its mechanism is not fully settled.