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TGF-β downregulation-induced cancer cell death is finely regulated by the SAPK signaling cascade

Zhezhu Han1,2, Dongxu Kang1,2, Yeonsoo Joo1,3

  • 1Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea.

Experimental & Molecular Medicine
|December 8, 2018
PubMed

Insights

Downregulating transforming growth factor-beta (TGF-β) in cancer cells activates stress pathways, leading to cancer cell death. This involves reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress, ultimately activating ASK1.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Transforming growth factor-beta (TGF-β) signaling is a critical factor in cancer progression and malignancy.
  • Increased TGF-β expression correlates with advanced cancer stages.

Purpose of the Study:

  • To investigate the impact of TGF-β downregulation on cancer cell death.
  • To elucidate the molecular mechanisms underlying TGF-β's role in cancer cell survival and apoptosis.

Main Methods:

  • Utilized adenoviruses expressing short hairpin RNAs to downregulate TGF-β1 and TGF-β2.
  • Analyzed the phosphorylation of stress-activated protein kinases (SAPKs) like p38 and JNK.
  • Measured reactive oxygen species (ROS) production and Akt activity.
  • Assessed changes in NOX4, Trx, GSTM1, and ASK1 interactions.
  • Investigated endoplasmic reticulum (ER) stress markers.

Main Results:

  • TGF-β downregulation increased SAPK phosphorylation (p38, JNK) and ROS production.
  • Akt was inactivated, and NOX4-derived ROS increased in a cell-type-specific manner.
  • Expression of Trx and GSTM1, ASK1 inhibitors, decreased.
  • ROS and ER stress disrupted ASK1-inhibitor interactions, leading to ASK1 activation.
  • Activated ASK1 induced cancer cell death via p38/JNK activation and ER stress.

Conclusions:

  • TGF-β downregulation triggers cytotoxic pathways in cancer cells.
  • The mechanism involves ROS production, ER stress, and ASK1 activation.
  • Targeting TGF-β signaling presents a potential therapeutic strategy for cancer treatment.

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