Oncogenic KRAS suppresses store-operated Ca 2+ entry and I CRAC through ERK pathway-dependent remodelling of STIM expression in colorectal cancer cell lines

Abstract

The KRAS GTPase plays a fundamental role in transducing signals from plasma membrane growth factor receptors to downstream signalling pathways controlling cell proliferation, survival and migration. Activating KRAS mutations are found in 20% of all cancers and in up to 40% of colorectal cancers, where they contribute to dysregulation of cell processes underlying oncogenic transformation. Multiple KRAS-regulated cell functions are also influenced by changes in intracellular Ca levels that are concurrently modified by receptor signalling pathways. Suppression of intracellular Ca release mechanisms can confer a survival advantage in cancer cells, and changes in Ca entry across the plasma membrane modulate cell migration and proliferation. However, inconsistent remodelling of Ca influx and its signalling role has been reported in studies of transformed cells. To isolate the interaction between altered Ca handling and mutated KRAS in colorectal cancer, we have previously employed isogenic cell line pairs, differing by the presence of an oncogenic KRAS allele (encoding KRAS), and have shown that reduced Ca release from the ER and mitochondrial Ca uptake contributes to the survival advantage conferred by oncogenic KRAS. Here we show in the same cell lines, that Store-Operated Ca Entry (SOCE) and its underlying current, I are under the influence of KRAS. Specifically, deletion of the oncogenic KRAS allele resulted in enhanced STIM1 expression and greater Ca influx. Consistent with the role of KRAS in the activation of the ERK pathway, MEK inhibition in cells with KRAS resulted in increased STIM1 expression. Further, ectopic expression of STIM1 in HCT 116 cells (which express KRAS) rescued SOCE, demonstrating a fundamental role of STIM1 in suppression of Ca entry downstream of KRAS. These results add to the understanding of how ERK controls cancer cell physiology and highlight STIM1 as an important biomarker in cancerogenesis.

ORAI channels and cancer

“…However, there may be cases, as recently suggested, where mutations may remodel SOCE, e.g. oncogenic KRAS induced changes in STIM1 expression via ERK signalling [17]. However, changes in a specific Ca 2+ influx pathway via an ORAI channel is unlikely to be a driver of transformation and ORAI channels are unlikely to ever be classified as oncogenes [10].…”

ERK is a Pivotal Player of Chemo-Immune-Resistance in Cancer

“…For instance, in breast cancer, ROS activates the PI3K/AKT/ERK axis, up-regulating cyclin D and CDK4,and stimulating the entry into S-phase [66]. Oscillations in intracellular calcium, controlled by K-RAS, increase the ERK-driven tumorigenesis in colorectal cancer [67]. The kinesin family member 15 (KIF15), which controls microtubule assembly and mitosis, activates the MEK/ERK axis, promoting pancreatic adenocarcinoma cell growth [68].…”

ER Ca2+ release and store-operated Ca2+ entry – partners in crime or independent actors in oncogenic transformation?

“…increase in PKB-dependent InsP3R phosphorylation). Alternatively, SOCE may be reduced as a strategy to lower ER Ca 2+ content and protect from apoptosis, as seen for example by our group [156], where SOCE was equally diminished in two different KRAS wt/G13D colorectal cancer cell lines bearing a different abundance of STIM1 (and STIM2, see later). This might seem counterintuitive but the demand for Ca 2+ signals during tumorigenic transformation presumably differs according to the stage of differentiation and functional requirements of the cell [34,49,157].…”