Abstract
Rigosertib, via reactive oxygen species (ROS), stimulates cJun N-terminal kinases 1/2 (JNK1/2), which inactivate RAS/RAF signaling and thereby inhibit growth and survival of tumor cells. JNK1/2 are not only regulated by ROS—they in turn can also control ROS production. The prooxidant and cell death function of p66Shc requires phosphorylation by JNK1/2. Here, we provide evidence that establishes p66Shc, an oxidoreductase, as a JNK1/2 effector downstream of Rigosertib-induced ROS production, DNA damage, and cell death. This may provide a common pathway for suppression of tumor cell growth by Rigosertib.
Highlights
Mutational activation of the three small G proteins HRAS, KRAS and NRAS is common in tumors, enabling them to interact with various effectors—among which the members of the serine-threonine kinases of the RAF family (ARAF, BRAF, CRAF), PI3K, and RalGDS feature prominently [1,2,3]
The p66Shc activation requires phosphorylation of S36 by JNK1/2, followed by additional phosphorylations on S139, T206, and S213 by PKCβ [11,14]. This process is responsible for the subsequent translocation of cytosolic p66Shc to the mitochondria, where it causes the production of reactive oxygen species (ROS) [13]
We addressed whether JNK1/2 activation results in the phosphorylation of S36 on p66Shc, an event that is essential for the activation of its prooxidant and pro-death activity [12]
Summary
Mutational activation of the three small G proteins HRAS, KRAS and NRAS is common in tumors, enabling them to interact with various effectors—among which the members of the serine-threonine kinases of the RAF family (ARAF, BRAF, CRAF), PI3K, and RalGDS feature prominently [1,2,3]. An alternative mechanism of Rigosertib action has been described whereby it interacts with the RAS-binding domains (RBDs) of RAS effectors This interferes with signal flow from oncogenic RAS [6]. Rigosertib activates cJun N-terminal kinases 1/2 (JNK1/2) that, in turn, phosphorylate the guanine nucleotide exchange factor (GEF) SOS and the RAF kinases CRAF and BRAF. This modification prevents RAS/RAF downstream signaling with negative effects on cell survival and proliferation. The p66Shc activation requires phosphorylation of S36 by JNK1/2, followed by additional phosphorylations on S139, T206, and S213 by PKCβ [11,14] This process is responsible for the subsequent translocation of cytosolic p66Shc to the mitochondria, where it causes the production of ROS [13]. Since Rigosertib activates JNK1/2 [7], we are interested in a possible p66Shc requirement for tumor-cell killing after Rigosertib treatment
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