Survival strategies of cancer cells: the role of macropinocytosis in nutrient acquisition, metabolic reprogramming, and therapeutic targeting

Abstract

Macropinocytosis is a nonselective form of endocytosis that allows cancer cells to largely take up the extracellular fluid and its contents, including nutrients, growth factors, etc. We first elaborate meticulously on the process of macropinocytosis. Only by thoroughly understanding this entire process can we devise targeted strategies against it. We then focus on the central role of the MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) in regulating macropinocytosis, highlighting its significance as a key signaling hub where various pathways converge to control nutrient uptake and metabolic processes. The article covers a comprehensive analysis of the literature on the molecular mechanisms governing macropinocytosis, including the initiation, maturation, and recycling of macropinosomes, with an emphasis on how these processes are hijacked by cancer cells to sustain their growth. Key discussions include the potential therapeutic strategies targeting macropinocytosis, such as enhancing drug delivery via this pathway, inhibiting macropinocytosis to starve cancer cells, blocking the degradation and recycling of macropinosomes, and inducing methuosis - a form of cell death triggered by excessive macropinocytosis. Targeting macropinocytosis represents a novel and innovative approach that could significantly advance the treatment of cancers that rely on this pathway for survival. Through continuous research and innovation, we look forward to developing more effective and safer anti-cancer therapies that will bring new hope to patients.Abbreviation: AMPK: AMP-activated protein kinase; ASOs: antisense oligonucleotides; CAD: carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase; DC: dendritic cell; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; ERBB2: erb-b2 receptor tyrosine kinase 2; ESCRT: endosomal sorting complex required for transport; GAP: GTPase-activating protein; GEF: guanine nucleotide exchange factor; GRB2: growth factor receptor bound protein 2; LPP: lipopolyplex; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; NSCLC: non-small cell lung cancer; PADC: pancreatic ductal adenocarcinoma; PDPK1: 3-phosphoinositide dependent protein kinase 1; PI3K: phosphoinositide 3-kinase; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns(3,4,5)P₃: phosphatidylinositol-(3,4,5)-trisphosphate; PtdIns(4,5)P₂: phosphatidylinositol-(4,5)-bisphosphate; PTT: photothermal therapies; RAC1: Rac family small GTPase 1; RPS6: ribosomal protein S6; RPS6KB1: ribosomal protein S6 kinase B1; RTKs: receptor tyrosine kinases; SREBF: sterol regulatory element binding transcription factor; TFEB: transcription factor EB; TNBC: triple-negative breast cancer; TSC2: TSC complex subunit 2; ULK1: unc-51 like autophagy activating kinase 1; UPS: ubiquitin-proteasome system.

Keywords: Anti-cancer therapies; MTORC1; MTORC2; macropinocytosis; metabolic reprogramming; methuosis.

Figure 1.

The process of macropinocytosis. Including signal activation (such as via EGF), actin cytoskeleton remodeling, formation of macropinosomes, maturation of macropinosomes, degradation and recycling of macropinosomes, and macropinosomes undergoing homotypic fusion to form larger vacuoles (methuosis).

Figure 2.

Composition of MTORC1 and MTORC2 core components. MTORC1: MTOR: a serine/threonine kinase that is the catalytic core of the complex. RPTOR: essential for substrate specificity and recruiting downstream effectors. MLST8: stabilizes the kinase domain of MTOR. AKT1S1/PRAS40: a negative regulator that inhibits MTORC1 activity when not phosphorylated. DEPTOR: another negative regulator that inhibits MTOR activity. MTORC2: MTORC2 also shares the MTOR kinase, MLST8, and DEPTOR, but contains unique components RICTOR, PRR5/PROTOR, and MAPKAP1/MSIN1. RICTOR: a defining component of MTORC2. PRR5/PROTOR1-PRR5L/PROTOR2: accessory components of MTORC2. MAPKAP1/MSIN1: essential for MTORC2 integrity and function. It interacts with RICTOR and contributes to the complex’s ability to phosphorylate specific substrates.

Figure 3.

Upstream regulation of MTORC1 and MTORC2. PI3K-AKT pathway activated by insulin; amino acids activate MTORC1 via the RRAG GTP enzyme; energy stress activated AMPK pathway; RAS activated RAF-MAP2K-MAPK pathway; MTORC2 as an effector of insulin-PI3K signaling.

Figure 4.

The major pathways downstream of MTORC1 signaling.

Figure 5.

The major pathways downstream of MTORC2 signaling.

Figure 6.

New anti-cancer therapies through macropinocytosis.