Anti-Cancer Strategy Based on Changes in the Role of Autophagy Depending on the Survival Environment and Tumorigenesis Stages

Abstract

Autophagy is a crucial mechanism for recycling intracellular materials, and under normal metabolic conditions, it is maintained at low levels in cells. However, when nutrients are deficient or under hypoxic conditions, the level of autophagy significantly increases. Particularly in cancer cells, which grow more rapidly than normal cells and tend to grow in a three-dimensional manner, cells inside the cell mass often face limited oxygen supply, leading to inherently higher levels of autophagy. Therefore, the initial development of anticancer drugs targeting autophagy was based on a strategy to suppress these high levels of autophagy. However, anticancer drugs that inhibit autophagy have not shown promising results in clinical trials, as it has been revealed that autophagy does not always play a role that favors cancer cell survival. Hence, this review aims to suggest anticancer strategies based on the changes in the role of autophagy according to survival conditions and tumorigenesis stage.

Keywords: alternative autophagy; anticancer drugs; canonical autophagy; cellular transformation; microenvironment; tumor.

Figure 1

The four stages of autophagy. Autophagy is a process divided into four main stages: initiation, phagophore nucleation, elongation, and fusion/degradation. During the initiation stage, signaling proteins respond to external factors such as stress stimuli to regulate autophagy. When cellular energy levels are low, AMPK directly activates ULK1 to induce autophagy, while the type I PI3K/AKT pathway inhibits it via mTOR. In the nucleation stage, BECN1 serves as a platform, forming core complexes with proteins like VPS34 (a type III PI3K), AMBRA, and ATG14L. The elongation stage involves two ubiquitin-like conjugation systems: LC3 and ATG12. ATG12 forms a complex with ATG5, playing a crucial regulatory role in early autophagosome formation and interacting with ATG16L to create larger multiprotein complexes. LC3 is activated by ATG7 and transferred to ATG3, where it binds to the lipid PE through the ATG12–ATG5 conjugate, producing LC3-II, a key marker of autophagy. Once the autophagosome is fully formed, it fuses with lysosomes to create autolysosomes, a process requiring SNARE proteins such as STX17, SNAP29, and VAMP8. In the autolysosome’s acidic environment, the inner membrane is degraded, and the contents are broken down by hydrolytic enzymes.

Figure 2

Autophagy modulators targeting each step of the autophagy pathway.

Figure 3

Anticancer drug development strategy based on the changing role of autophagy in tumorigenesis stages. Canonical ATG5/LC3-dependent autophagy suppresses tumor formation in the early stages of tumorigenesis but plays a crucial role in cell survival during the advanced stages of cancer. Therefore, for effective tumor therapy, it is important to use inducers of canonical autophagy during the initiation stage of tumor formation and inhibitors during the progression stage. Our research indicates that in challenging microenvironments for tumor cell survival, such as high cell confluency and exposure to anticancer drugs, alternative autophagy is more critical for maintaining cell survival than canonical autophagy. Thus, from a therapeutic perspective for advanced tumors, it is vital to develop anticancer strategies that focus on using inhibitors of alternative autophagy rather than canonical autophagy, depending on the tumor microenvironment.