Specific signaling pathways mediated programmed cell death in tumor microenvironment and target therapies

Abstract

Increasing evidence has shown that programmed cell death (PCD) plays a crucial role in tumorigenesis and cancer progression. The components of PCD are complex and include various mechanisms such as apoptosis, necroptosis, alkaliptosis, oxeiptosis, and anoikis, all of which are interrelated in their functions and regulatory pathways. Given the significance of these processes, it is essential to conduct a comprehensive study on PCD to elucidate its multifaceted nature. Key signaling pathways, particularly the caspase signaling pathway, the RIPK1/RIPK3/MLKL pathway, and the mTOR signaling pathway, are pivotal in regulating PCD and influencing tumor progression. In this review, we briefly describe the generation mechanisms of different PCD components and focus on the regulatory mechanisms of these three major signaling pathways within the context of global PCD. Furthermore, we discuss various tumor therapeutic compounds that target different signaling axes of these pathways, which may provide novel strategies for effective tumor therapy and help improve patient outcomes in cancer treatment.

Keywords: Caspase; MLKL; MTOR; Programmed cell death; RIPK1; RIPK3; Tumor.

Fig. 1

Caspase signaling can induce endogenous apoptosis through caspase 8,10,7,3 and exogenous apoptosis through the cascade of caspase3,6,7,9,10. Inhibition of Caspase 8 can induce necroptosis. Pyroptosis and autophagy can be induced through caspase 1. Caspase3,6,9 -mediated Beclin-1 degradation and Caspase 2 both inhibit autophagy

Fig. 2

The RIPK1/RIPK3/MLKL signaling pathway is involved in tumor cells through Complex I (TRADD, TRAF, cIAPs, LUBA and RIPK1) and Complex IIa(TRADD1, RIPK1,FADD, and pro-caspase 8) induces apoptosis, necroptosis and prevents PANoptosis through Complex IIb (RIPK1, RIPK3, MLKL). Phosphorylated MLKL can promote mitochondrial ROS generation, which induces NETosis and ferroptosis. Ubiquitinated RIPK3 can inhibit this process while inducing autophagy. Phosphorylated RIPK1 can also induce autophagy, which can promote the reduction of ROS production and NADPH production, thereby inducing anoikis

Fig. 3

In the mTOR signaling pathway, PI3 K/AKT/mTOR axis can induce the occurrence of apoptosis. mTORC1 complex (mLST8, RAPTOR, DEPTOR, Tti1, Tel2, PRAS40) can induce anoikis. mTORC1 can promote autophagy through ULK1 complex and VPS34 complex, and can promote necroptosis through autophagy. mTORC1 can inhibit Fe2 + and thus ferroptosis. AMPK/mTOR axis inhibits ferroptosis and necroptosis by regulating the system Xc-glutathione (GSH)-GPX4 axis to inhibit ROS generation