Related Experiment Video

Updated: May 21, 2026

Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen
19:44

Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen

Published on: May 30, 2012

MAPK14/p38α confers irinotecan resistance to TP53-defective cells by inducing survival autophagy

Salome Paillas1, Annick Causse, Laetitia Marzi

  • 1Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.

Autophagy
|June 1, 2012
PubMed

Insights

Mitogen-activated protein kinase (MAPK) MAPK14/p38α activation promotes colon cancer cell survival by inducing autophagy, a mechanism that confers resistance to irinotecan therapy. Inhibiting MAPK14/p38α or autophagy sensitizes cells to chemotherapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Mitogen-activated protein kinase (MAPK) MAPK14/p38α has been implicated in colon cancer drug resistance.
  • Autophagy plays a role in cancer cell resistance to chemotherapy and radiation.

Purpose of the Study:

  • To investigate the cellular mechanisms of colon cancer resistance to camptothecin-related drugs, specifically irinotecan.
  • To elucidate the relationship between MAPK14/p38α, autophagy, and irinotecan resistance in TP53-ablated colon cancer cells.

Main Methods:

  • Utilized HCT116 human colorectal adenocarcinoma cells with genetically ablated TP53 (HCT116-TP53KO).
  • Overexpressed constitutively active MAPK14/p38α.
  • Assessed cell sensitivity to SN-38 (irinotecan metabolite), cell proliferation, and autophagy induction.
  • Investigated the effect of inhibiting MAPK14/p38α or autophagy on drug sensitivity.

Main Results:

  • Overexpression of active MAPK14/p38α decreased sensitivity to SN-38, inhibited proliferation, and induced survival-autophagy in HCT116-TP53KO cells.
  • SN-38-induced autophagy was dependent on MAPK14/p38α activation.
  • Inhibition of either MAPK14/p38α or autophagy sensitized HCT116-TP53KO cells to irinotecan therapy.
  • The role of autophagy in drug resistance was dependent on MAPK14/p38α.

Conclusions:

  • A novel mechanism of resistance to camptothecin-related drugs involves SN38-induced activation of MAPK14/p38α, which triggers survival-promoting autophagy.
  • This pathway protects colon tumor cells from cytotoxic effects of irinotecan.
  • Colon cancer cells can be sensitized to irinotecan by inhibiting either MAPK14/p38α or autophagy.
Keywords:
MAPK14/p38chemotherapycolon canceririnotecan resistancesurvival autophagy

Related Concept Videos

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 rapamycin-insensitive companion...
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...
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 daughter...
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...