Lysosomal Autophagy and Drug Resistance in Cancer: Overcoming Chemoresistance

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Introduction

Cancer is a most complex and challenging disease to treat because so many therapies readily lose their ability to control and ultimately eradicate cancer. Chemoresistance, the result of cancer cells that beat the odds and hide from the effects of chemotherapy, has been a troublesome blockade to traditional cancer treatment. A critical mechanism that underlies this resistance is autophagy, as elucidated by lysosomal autophagy. This is a highly conserved cellular process called autophagy, in which cellular constituents are degraded and recycled in cancer cells, exploiting autophagy for survival from stress, for example, exposure to chemotherapy. In particular, lysosomal autophagy is extremely important for the cancer cell’s capacity to withstand chemotherapy by rendering chemotherapy agents degrade or recycling damaged organelles or proteins to help maintain cell viability. Here we discuss the role of lysosomal autophagy in drug resistance and develop strategies to overcome chemoresistance in cancer therapy.

Understanding Autophagy in Cancer

Autophagy is a cellular process in which the cell ingests degrades and recycles damaged organelles, proteins, and other cellular components and keeps cell homeostasis. They are formed by autophagosomes, double-membered vesicles that enclose contents, which fuse with lysosomes where contents are degraded. Autophagy is under normal physiological conditions a survival mechanism when nutrient deprivation or other stressors occur. However, another aspect of autophagy goes into play in cancer. It was established that autophagy may suppress tumor initiation by clearing damaged organelles and preventing the building up of toxic material but could also promote tumor survival by helping cancer cells survive metabolic stress and be resilient to therapy.

Autophagy is often dysregulated in cancer to the point that tumor cells exploit it to allow continued growth, survive under hostile conditions, and crucially, survive chemotherapy. Of special interest is lysosomal autophagy, through which cancer cells can elude chemotherapeutic stress. Lysosomal autophagy recycles damaged cellular components as well as degrades chemotherapeutic agents and, in doing so, participates in chemoresistance development that renders such standard treatments less effective.

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Lysosomes and Their Role in Chemoresistance

Lytic organelles (known as lysosomes) include membrane-bound, degradative organelles that contain hydrolases that degrade cellular waste, primarily including proteins, lipids, and nucleic acids. Indeed, in the cancer cell, lysosomes are more than just a cellular dustbin for waste disposal—they contribute actively to the regulation of cell metabolism, cell signaling pathways, and even cell death. The altered lysosomal function is often manifested in cancer cells and enables their survival under therapy pressure.

Drug sequestration by lysosomes is one of the major ways that lysosomes were found to play a role in chemical resistance. Chemotherapy agents, such as doxorubicin, that are used weakly basic can be trapped within the acidic lysosomal environment. Inside, these drugs, however, are rendered ineffective as they are sequestered away from the intracellular targets to which they must affect to have toxic effects on cancer cells. Lysosomal sequestration of this drug lowers the cytoplasmic concentration of the active drug, reduces drug-induced apoptosis, and allows cancer cells to survive chemotherapy.

In addition, in cancer cells, lysosomal biogenesis is often upregulated, which allows them to accumulate a higher capacity for lysosomal degradation of chemotherapeutic agents and recycling of cellular components. The increased lysosomal activity increases cancer cell survival and resistance that otherwise would be caused by chemotherapy stress.

Autophagy and Tumor Microenvironment

The interaction between tumor microenvironment (TME) and cancer cells involves autophagy and has a critical role in determining the sensitivity/tolerance of the cancer cells in response to therapy. In the TME, cancer cells experience nutrient-deprived as well as hypoxic conditions, and both provide the basis for the induction of autophagy as a survival mechanism. Given that, lysosomal autophagy also allows cancer cells to break down intracellular components to generate energy and sustain growth in an otherwise hostile environment.

Furthermore, we have shown that autophagy in cancer-associated fibroblasts (CAFs), which are the main component of TME, plays an important role in the progression of cancer and resistance to therapy. CAFs undergo autophagy to generate metabolic intermediates that can be recycled by cancer cells via the endocytic pathway as an alternative source of nutrients. It is a symbiotic relationship between CAFs and cancer cells that allows the tumor to survive, even in the face of metabolic stress and in a chemoresistant setting.

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Targeting Lysosomal Autophagy to Overcome Chemoresistance

With a known role in chemoresistance, targeting the lysosomal autophagy pathway has become a promising approach to increasing the efficacy of chemotherapy. Inhibiting lysosomal autophagy while at the same time restoring the sensitivity of cancer cells to treatment is being investigated using several approaches.

Lysosomal Inhibitors: CreArray drugs that directly block lysosomal function, such as chloroquine (CQ) and hydroxychloroquine (HCQ), have been repurposed for their potential reverse chemoresistance. These agents up-regulate the pH within lysosomes such that the degradation capability of lysosomes is impaired. This results in the accumulation of damaged organelles and proteins, with subsequent cell death occurring as the result of the disruption of cellular lysosomal function inhibiting the degradation of autophagic cargo. This combined lysosomal inhibitor plus chemotherapy studies have shown the potential to enhance the cytotoxic effects of treatment by blocking the survival mechanism of cancer cells using autophagy.

Autophagy Modulators: A further approach involves autophagy modulators, which act either by blocking autophagosome formation or by blocking autophagosome-lysosome fusion. For inhibition of the autophagic process at various stages, agents such as bafilomycin A1 and wortmannin have been explored. These agents, by blocking autophagosome formation or autophagosome-lysosome fusion, are able to disrupt the recycling capacity of cancer cells to the extent that they become sensitive to chemotherapy.

Targeting mTOR Pathway: O Springer Science+Business Media, LLC 2009 The mammalian target of the rapamycin (mTOR) pathway is a key regulator of autophagy. Inhibiting mTOR can inspire autophagy, which causes too much cellular component degradation, which will eventually lead to cell death. Although its inhibition is beneficial in the context of cancer therapy, in the presence of lysosomal inhibitors, inhibition of mTOR prevents the upregulation of compensatory survival pathways and enhances chemotherapy efficacy.

Combination Therapies: Preclinical trials have shown promise for combining autophagy inhibitors with standard chemotherapy agents. Combining CQ or HCQ with agents such as doxorubicin, cisplatin, or paclitaxel has been shown to rescue cells from resistance to such agents. The combination approach kills cancer cells that have become reliant on autophagy to survive, preventing them from skipping over chemotherapy-induced cell death.

Challenges and Future Directions

Several challenges remain for lysosomal autophagy targeting to overcome chemoresistance. Inhibition of autophagy is one of the major concerns because it could also affect normal cells. A major constituent of cell homeostasis is autophagy and suppression of such a process in normal cells could cause unintended side effects that include a heightened risk of infections or neurodegenerative diseases. Consequently, selective autophagy inhibitors are being developed that target cancer cells.

The complexity of autophagy regulation in different types of cancer is another challenge. Depending on the context, autophagy can have tumour-suppressive and tumor-promoting effects. For this reason, a one-size-fits-all inhibition of autophagy may not be the appropriate treatment for all cancer types. Chemoresistance likely will be overcome in more successful ways with personalized approaches that are tuneable based on the autophagic activity and lysosomal function of a given tumor.

Finally, future research will also need to identify biomarkers that would predict a tumor’s reliance on autophagy for survival. It would keep patients who stand to most benefit from the therapies targeting autophagy from unnecessary exposure to toxicity while improving treatment outcomes.

Conclusion

Cancer cells have developed strategies to bypass the cytotoxic effects of chemotherapy, in part by virtue of a role for Lysosomal autophagy. Cancer cells can sidestep cell death by sequestering chemotherapeutic agents and recycling damaged cellular components, thus avoiding treatment. Chemoresistance can be broken by targeting lysosomal autophagy, thus increasing the efficiency of chemotherapy. Despite this, the development of selective autophagy inhibitors alongside understanding the combinatorial role of autophagy in different cancer types remains a challenge. If research continues, new hope for patients with chemoresistant cancers might be novel therapies that disrupt lysosomal autophagy.

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