Mahmoud Ahmed

Postdoc - Biomedicine

A cell eating itself, leveraging autophagy to treat cancer

January 05, 2022

What is autophagy?

Autophagy is a process by which the cell can maintain and recycle its components. The process starts by forming a membrane around the target. This structure then is fused with lysosomes which contain enzymes to lyse and degrade the contents. More selective forms of autophagy exist to specifically target organelles, proteins, or RNAs for degradation. Autophagy removes damaged intracellular organelles and recycles them to build other components or generate energy. Beyond a certain point, as cells are irreparably damaged, autophagy triggers cell death. A lot has been shown in ways of benefits to the cell of this elaborate process cells have evolved to maintain themselves. It is, however, a double-edged sword. Cancer cells as much as normal cells take advantage of this maintenance and self-renewal to survive and grow.

The dual role of autophagy

In normal cells, these functions are cytoprotective and, in the least, helps maintain the integrity of the tissue or organs by removing damaged cells. The broad span of functions lends itself to speculations about how autophagy contributes to cancer development and progression. Indeed, in the context of cancer, the same cytoprotective functions of autophagy can be harmful to the body. For instance, autophagy maintains the inside of the cell by removing damaged parts, which could help the cancerous cell divide indefinitely. Similarly, autophagy could provide energy for metabolically demanding processes such as the transitioning of cancer cells to more aggressive or metastatic forms.

Signaling cell death and metabolic changes

Autophagy is linked to several key signaling pathways in the cell. These pathways help autophagy respond to the outside environment as well as the changes in the inside state of the cell. Several of these pathways are hijacked in cancer cells to gain independence from the outside signaling and direct the cell energy to unlimited growth. The autophagy-triggered apoptosis is one example of a signaling pathway that is amenable to modifications in cancer since cancer cells can evade it continuously. Changes in metabolism in cancer cells are also a suspect for involving autophagy, which is tightly linked to the availability of nutrients. These pathways and others are among the apparent targets for modification in cancer development and therapy.

Inhibiting autophagy as cancer therapy

Autophagy inhibitors are the most tried class of drugs that modify autophagy to treat cancer. Several compounds have been shown in pre-clinical and clinical studies to favor cancer cell death either as a lone treatment or as an adjuvant for other drugs. The bulk of this work focused on modulating autophagy late in cancer development or preventing its progression to aggressive and metastatic disease. The drugs were also shown to reduce chemotherapy resistance and enhance the effect of drug therapeutics.

Activating autophagy in early-stage cancer

Could targeting autophagy earlier in cancer development procure the same benefits? Indeed a body of work is showing that activating autophagy rather than inhibiting it would be beneficial. Leveraging the role of autophagy in degrading mesenchymal transcription factors, in particular, seem to reduce the production of the protein needed for the transition to metastatic cells. Strategies for inducing autophagy, therefore, are advantageous in an earlier stage of the disease.

The unintended consequences of modulating autophagy

Multiple drugs modify autophagy only incidentally during their course of treatment. Others have their mechanism of action in treating cancer independent of their effect on autophagy. In either case, deliberately stabilizing autophagy or enhancing its function could bear on the drugs' action. Studying how conventional cancer therapies modulate autophagy in their regular course of action is poignant to take advantage of autophagy features. A number of autophagy inhibitors are used as drug adjuvants to do precisely that. As several cancer drugs were found to induce autophagy, and this induction was found to be cytoprotective of the cancer cells, inhibiting autophagy seemed like a sensible strategy to boost the effectiveness of the drugs.

The road forward

A granular targeting of autophagy functions would seem reasonable. However, this remains speculative since few studies have explored the subtypes and selective autophagy in this context. Less is known about the role of autophagy in indirectly modifying the cancer microenvironment or the immune response that it triggers. Modifying either has succeeded as cancer therapies and, therefore, exploring how they relate to autophagy represents future research avenues.