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Morphological transformation induced by activation of the mitogen-activated protein kinase pathway requires
M W Strobeck1, M Okuda, H Yamaguchi
1Department of Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0521, USA.
Abstract:
Transformation of fibroblasts by various oncogenes, including ras, mos, and src accompanies with characteristic morphological changes from flat to round (or spindle) shapes. Such morphological change is believed to play an important role in establishing malignant characteristics of cancer cells. Activation of the mitogen-activated protein kinase (MAPK) pathway is a converging downstream event of transforming activities of many oncogene products commonly found in human cancers. Intracellular calcium is known to regulate cellular morphology. In fibroblasts, Ca2+ influx is primarily controlled by two types of Ca2+ channels (T- and L-types). Here, we report that the T-type current was specifically inhibited in cells expressing oncogenically activated Ras as well as gain-of-function mutant MEK (MAPK/extracellular signal-regulated kinase (ERK) kinase, a direct activator of MAPK), whereas treatment of ras-transformed cells with a MEK-specific inhibitor restored T-type Ca2+ channel activity. Using a T-type Ca2+ channel antagonist, we further found that suppression of the T-type Ca2+ channel by the activated MAPK pathway is a prerequisite event for the induction and/or maintenance of transformation-associated morphological changes.
Insights
Oncogenes like Ras activate the MAPK pathway, inhibiting T-type calcium channels and altering cell shape. This study reveals T-type calcium channel suppression is key to cancer cell morphology changes.
Area of Science:
- Cell Biology
- Oncology
- Molecular Biology
Background:
- Oncogene activation, such as by Ras, induces fibroblast morphological changes crucial for cancer malignancy.
- The mitogen-activated protein kinase (MAPK) pathway is a common downstream target of oncogenes.
- Intracellular calcium, regulated by T- and L-type channels, influences cell morphology.
Purpose of the Study:
- To investigate the role of T-type calcium channels in oncogene-induced fibroblast transformation.
- To determine the relationship between MAPK pathway activation and T-type calcium channel function.
- To elucidate the contribution of T-type calcium channel suppression to cancer cell morphology.
Main Methods:
- Utilized oncogenically activated Ras and mutant MEK in fibroblast cell models.
- Assessed T-type calcium channel currents in response to oncogene and pathway activation.
- Employed a MEK-specific inhibitor and a T-type calcium channel antagonist.
Main Results:
- T-type calcium channel currents were inhibited in cells expressing activated Ras or mutant MEK.
- MEK inhibition restored T-type calcium channel activity in ras-transformed cells.
- Suppression of T-type calcium channels by the MAPK pathway is essential for transformation-associated morphological changes.
Conclusions:
- The MAPK pathway, activated by oncogenes, suppresses T-type calcium channels.
- Inhibition of T-type calcium channels is a critical step in oncogene-induced cell transformation and cancer progression.
- Targeting T-type calcium channels may offer a novel therapeutic strategy for cancers driven by these oncogenic pathways.