The role of autophagy and metabolism in cancer
The main mechanism behind the growth and progression of cancer cells is altered metabolic states which are closely associated with autophagic modulation in cancer cells
Autophagy refers to the process by which a cell consumes its own damaged cellular organelles during starvation. It plays an important role in the survival of the cellular structure by modulating the metabolic switches during stress conditions.
Autophagy controls the physiological and pathological processes at the cellular level which play an important role in the survival of cancer cells through the recycling of nutrients.
To sustain the metabolic function of the mitochondria and energy homeostasis – the process which regulates food intake and energy expenditure – starvation-induced autophagy reprocesses intracellular components into metabolic pathways, which are basically a linked series of chemical reactions occurring within a cell.
The metabolic and biosynthetic pathways reutilize and recycle the degraded ‘breakdown products’ that are released from lysosomes, which are the enzymes responsible for breaking down proteins, carbohydrates, and lipids.
Autophagy restricts tissue damage, oxidative stress, and oncogenic signaling – intricate networks of multiple signaling pathways that control the growth and progression of a tumor – through the prevention of toxic accumulation of damaged cellular organelles and proteins, which helps inhibit cancer cell survival.
Cancer usually develops when signaling pathways associated with the normal cell cycle are disturbed because of genomic instability. Before genomic instability leads to cell death, autophagy gets activated to prevent cell death.
Autophagy mainly contributes to the fitness of cells and cellular survival, which is triggered by cellular stress such as nutrient loss, deprivation of growth factors, oxidative stress, infection, and hypoxia. Furthermore, it plays an important role in maintaining the status of cellular homeostasis through the selective removal of non-functional or damaged proteins and organelles.
Autophagy has a huge impact on cancer cell survival and cancer progression.
Autophagy can be classified into three subcategories depending on its regulation:
- Macro-autophagy and
- Chaperone-mediated autophagy
Cancer represents hundreds of different diseases, and autophagy has a vital role to play in metabolism, protein, and organelle quality control in cancer cells. Autophagy stimulation prevents the initiation of several diseases, including cancer. As autophagy stimulation has great preventive and therapeutic value, this can be accomplished with periodic fasting.
In the last two decades, we have clearly understood the process of reprogramming of metabolic switches of cancer cells for their survival and growth in which autophagy plays an important role. One such metabolic effect in cancer cells is the ‘Warburg phenomenon’, where cancer cells utilize a hundred times more glucose than normal cells because of impaired mitochondrial activity.
While describing what causes cancer, Dr. Otto Heinrich Warburg, Nobel Laureate, 1931, for Physiology or Medicine, wrote,“Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause. Summarized in a few words, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar. All normal body cells meet their energy needs by respiration of oxygen, whereas cancer cells meet their energy needs in great part by fermentation.”
The crosstalk between reprogramming of metabolic switches and autophagy leads to the development of stemness, which is the capability of a cell for self-renewal and differentiation, metastasis, and drug resistance in cancer cells. Autophagy facilitates the survival of cancer cells through metabolic remodeling which makes them highly reliant on this mechanism for their survival. Targeting autophagy and altered metabolic switches in cancer cells could be an important therapeutic approach, in combination with conventional chemo and radiotherapy.
Cancer is now responsible for more deaths around the world than cardiac arrest. Though solid tumors are highly heterogeneous, the main mechanism behind the growth and progression of cancer cells is altered metabolic states (mainly glycolysis) which are closely associated with the autophagic modulation in cancer cells.
We have previously demonstrated that prolonged activation or suppression of autophagy in cancer cells leads to apoptosis and finally cell death. Our recent study suggests that blocking of glycolysis leads to the immediate death of cancer cells.
In this project, we have used a combinatorial therapeutic approach to block the metabolic and autophagy signaling together, to inhibit cancer growth and progression.
Together with other cancer therapeutic approaches, inhibition of metabolic and autophagy signaling can be an effective therapeutic strategy to treat cancer patients and minimize the rate of drug resistance and tumor reoccurrence.
“The role of autophagy and metabolism in cancer” project is supported by Science and Engineering Research Board (SERB), Government of India. Project No ECR/2016/001489 (SERB Qualified Unique Identification Document: SQUID-1982-DK-3962) and Indian Council of Medical Research (ICMR), New Delhi, Government of India (Project No 3/2/2/82/2022-NCD-III).
(The author is Senior Associate Professor at School of Health Sciences, UPES, Dehradun.)