Related Experiment Video

Updated: Aug 24, 2025

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
07:39

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

227

RagC GTPase regulates mTOR to promote chemoresistance in senescence-like HepG2 cells

Wei Jiang1,2, Zhenglin Ou1,2, Qin Zhu1,2

  • 1Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Frontiers in Physiology
|October 21, 2022
PubMed

Insights

Targeting RagC and Rheb GTPases can overcome therapy resistance in senescent liver cancer cells. Inhibiting autophagy-lysosomes also sensitizes these cells to chemotherapy, offering new treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Cancer therapies like radiotherapy and chemotherapy can induce a senescence-like state in cancer cells.
  • This senescence-like state is associated with therapy resistance and cancer relapse.
  • Mammalian target of rapamycin (mTOR) is hyperactivated in senescent cells, but the underlying mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the roles of mTOR-regulated GTPases in senescence-like liver cancer cells.
  • To elucidate the mechanisms by which these GTPases contribute to drug resistance.
  • To explore potential therapeutic strategies targeting these pathways.

Main Methods:

  • Examined the requirement of specific GTPases (RagC, Rheb, Rab1A, Rab5, Arf1) for mTOR activation in proliferating and senescence-like HepG2 liver cancer cells.
  • Assessed the impact of knocking down GTPases on drug resistance in senescence-like cells.
  • Investigated the role of autophagy-lysosome activity and its inhibition on mTOR signaling and chemosensitivity.
  • Correlated GTPase expression with patient prognosis in liver cancer.

Main Results:

  • Only RagC and Rheb GTPases, not Rab1A, Rab5, or Arf1, were essential for mTOR activation in senescence-like HepG2 cells.
  • Knocking down RagC and Rheb significantly reduced the drug resistance of senescence-like HepG2 cells.
  • Increased autophagic and lysosomal activity was observed in senescence-like cells.
  • Pharmacological inhibition of autophagy-lysosome decreased mTOR activity and enhanced sensitivity to trametinib, cisplatin, and doxorubicin.
  • Higher expression of RagC and Rheb in liver cancer patients correlated with unfavorable prognosis.

Conclusions:

  • RagC and Rheb GTPases play a critical role in mediating mTOR activation and drug resistance in senescence-like liver cancer cells.
  • Targeting the Rag-Rheb GTPase pathway presents a potential strategy for overcoming therapy resistance.
  • Inhibition of autophagy-lysosome pathways can re-sensitize resistant senescent liver cancer cells to chemotherapy.
  • These findings have significant implications for developing novel second-line treatments for liver cancer.
Keywords:
GTPasechemoresistanceliver cancermTORsenescence

More Related Videos

Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method08:04

Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method

Published on: October 23, 2018

19.1K
Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer06:51

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Published on: July 21, 2018

18.0K

Related Concept Videos

mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.9K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.8K
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
4.1K
The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
6.4K
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
35.6K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K