KRAS, but not HRAS, suppresses non-canonical WNT/Ca2+ signaling to promote tumorigenesis.
Major finding: KRAS, but not HRAS, suppresses non-canonical WNT/Ca2+ signaling to promote tumorigenesis.
Mechanism: KRAS binds CALM2 to inhibit FZD8 expression and ease CAMK2 repression of the stem-like phenotype.
Impact: The isoform-specific tumorigenic activity of mutant KRAS may be therapeutically targeted.
Members of the RAS oncogene family – HRAS, KRAS, and NRAS – share a high degree of sequence homology and, when mutated, activate similar signaling pathways. However, KRAS is uniquely mutated in specific tumor types, suggesting that KRAS plays a distinct role in tumorigenesis. To further characterize the isoform-specific tumor-promoting properties of KRAS, Wang and colleagues compared the effects of mutant HRAS and mutant KRAS on tumorigenic potential. Although both mutant HRAS and mutant KRAS exerted similar effects on canonical RAS signaling, only mutant KRAS promoted stem-like behavior and exhibited greater tumor-initiating potential both in vitro and in vivo. Profiling of stem cell–related genes showed that expression of mutant KRAS, but not mutant HRAS, resulted in downregulation of frizzled 8 (FZD8), a major regulator of the non-canonical WNT/calcium (Ca2+) pathway, and suppression of canonical WNT/β-catenin signaling in a genetically engineered mouse model (GEMM) inducibly expressing mutant Kras or mutant Hras from the endogenous Kras locus. Mechanistically, calmodulin (CALM2) preferentially bound to KRAS, but not HRAS or NRAS, resulting in the inhibition of calmodulin kinase II (CAMK2) phosphorylation, which led to decreased transcription of FZD8. Consistent with these findings, inhibition of CAMK2 or depletion of FZD8 enhanced the tumorigenicity of mutant HRAS–expressing cells, whereas restoration of FZD8 expression abrogated KRAS-driven tumor formation. Furthermore, stimulation of KRAS phosphorylation via treatment with prostratin, a non–tumor promoting activator of protein kinase C, disrupted the KRAS–calmodulin interaction, resulting in increased CAMK2 activation and decreased β-catenin activity. Prostratin treatment suppressed KRAS-driven human pancreatic cancer cell growth both in vitro and in vivo in xenograft and orthotopic models. Similarly, treatment of a GEMM of papilloma with prostratin resulted in the suppression of tumor formation in mice expressing mutant Kras, but not mutant Hras. Together, these findings demonstrate the tumor-type specific action of RAS isoforms and identify a potential therapeutic KRAS-targeting strategy.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
- ©2016 American Association for Cancer Research.