Redox Control of the Dormant Cancer Cell Life Cycle

Abstract

Following efficient tumor therapy, some cancer cells may survive through a dormancy process, contributing to tumor recurrence and worse outcomes. Dormancy is considered a process where most cancer cells in a tumor cell population are quiescent with no, or only slow, proliferation. Recent advances indicate that redox mechanisms control the dormant cancer cell life cycle, including dormancy entrance, long-term dormancy, and metastatic relapse. This regulatory network is orchestrated mainly through redox modification on key regulators or global change of reactive oxygen species (ROS) levels in dormant cancer cells. Encouragingly, several strategies targeting redox signaling, including sleeping, awaking, or killing dormant cancer cells are currently under early clinical evaluation. However, the molecular mechanisms underlying redox control of the dormant cancer cell cycle are poorly understood and need further exploration. In this review, we discuss the underlying molecular basis of redox signaling in the cell life cycle of dormant cancer and the potential redox-based targeting strategies for eliminating dormant cancer cells.

Keywords: ROS; cancer dormancy; cancer therapy; redox signaling.

Figure 1

Model of tumor burden and redox level in cancer cell dormancy. Primary tumors rely on mild oxidative stress that increases ROS levels beyond the tumorigenesis threshold to proliferation. While under therapeutic conditions, the ROS level may be beyond the elimination threshold to rapidly decrease tumor mass. Several cancer cells (including residual cells and disseminated cells) may reprogram and survive in a redox level lower than normal cells and enter dormancy. When some dormant cancer cells awaken in the tumor population, the redox level may again exceed the tumorigenesis threshold. The tumor proliferates slowly under the clinical threshold, called tumor mass dormancy. Once the tumor mass exceeds the clinical threshold, the tumor has relapsed. Blue arrows represent potential strategies to conduct antioxidant therapy to treat tumors; red arrows represent potential oxidant-dependent therapy. (a) Strategy to kill dormant cancer cells through excessive ROS; (b) Strategy for reawaking dormant cancer cells to sensitize cancer cells to anti-proliferation drugs; (c) Strategy using antioxidant to keep dormant cancer cells from awaking; (d) Chemotherapy on recurrent tumors, but may enter into another life cycle of dormant cancer cells.

Figure 2

Model of dormancy entrance. The balance between proliferation and dormancy may be partly dependent on the ratio of p-p38 and p-ERK1/2. Redox can activate TGF-β2 and inactivate integrins to activate p38 and inhibit activation of ERK1/2, as well as to modify ER chaperone BiP for release from key regulators of ER-stress signaling, thus activating ER-stress signaling and promoting cell survival and growth arrest. Redox-activated TGF-β1 and Fyn can activate ERK1/2 to promote cell proliferation, while integrins activate when it is not redox-modified. HIF-1α is inhibited under normoxia through redox modification mediated by PHDs and FIHs. Under hypoxia conditions, HIF-1α may translocate to the nucleus and promote transcription of dormant-related genes. ER, endoplasmic reticulum; ERK1/2, extracellular signal-regulated kinase 1/2; FIHs, factor inhibiting HIF-1; HIF-1α, hypoxia-inducible transcription factors 1α; TGF-β2, transforming growth factor β2.

Figure 3

Dormant-dependent microenvironment and intrinsic supportive signaling. Interactions between immune cells and cytokines balance the entrance and escape of dormancy. Osteoblasts, M2 macrophages, and T regular cells are considered protectors of cancer dormancy, while osteoclasts, M1 macrophage, and adipocytes may break cancer dormancy. Redox control of dormant sustaining mechanisms. Redox may activate FOXO to bind with β-catenin to promote transcription of dormancy-related genes competitively. Upon oxidative stress, KEAP1 can be inactivated and release NRF2 to translocate into the nucleus, thus promoting transcription of Notch1 and SHH. Wnt, Notch, and Hedgehog signaling may sustain cancer dormancy through transcription of stemness-related genes. Oxidative stress may activate autophagy by impairing the integrin/PI3K/Akt/mTOR axis, which impairs autophagy by inactivating ATG4, ATG7, and ATG3. FOXO, forkhead box O; KEAP1, Kelch-like ECH-associated protein 1; mTOR, mammalian target of rapamycin; NRF2, nuclear factor erythroid 2-related factor 2; PI3K, phosphoinositide 3-kinase; SHH, sonic hedgehog.

Figure 4

Strategies targeting dormancy from a redox perspective. (a) Keep dormant cancer cells asleep. After cancer therapy, dormant cancer cells may remain viable and remain at low redox levels. Antioxidant treatment may prevent dormant cancer cells from reactivating; (b) Awaken dormant cancer cells. Oxidants are used to reawaken dormant cancer cells, thus sensitizing them to anti-proliferation agents; (c) Kill dormant cancer cells. Oxidative phosphorylation inhibitors, autophagy inhibitors, and ferroptosis inducers can be used to eliminate dormant cancer cells.