Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy.

Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress response programs that counteract the inherent toxicity of such aberrant signaling. Although inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause lethality. We show here that inhibition of protein phosphatase 2A (PP2A) hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells. Genetic and compound screens identify combined inhibition of PP2A and WEE1 as synergistic in multiple cancer models by collapsing DNA replication and triggering premature mitosis followed by cell death. This combination also suppressed the growth of patient-derived tumors in vivo. Remarkably, acquired resistance to this drug combination suppressed the ability of colon cancer cells to form tumors in vivo. Our data suggest that paradoxical activation of oncogenic signaling can result in tumor-suppressive resistance. Significance: A therapy consisting of deliberate hyperactivation of oncogenic signaling combined with perturbation of the stress responses that result from this is very effective in animal models of colon cancer. Resistance to this therapy is associated with loss of oncogenic signaling and reduced oncogenic capacity, indicative of tumor-suppressive drug resistance.

Loss of DUSP3 activity radiosensitizes human tumor cell lines via attenuation of DNA repair pathways.

BACKGROUND: Radiotherapy causes the regression of many human tumors by increasing DNA damage, and the novel molecular mechanisms underlying the genomic instability leading to cancer progression and metastasis must be elucidated. Atypical dual-specificity phosphatase 3 (DUSP3) has been shown to down-regulate mitogen-activated protein kinases (MAPKs) to control the proliferation and apoptosis of human cancer cells. We have recently identified novel molecular targets of DUSP3 that function in DNA damage response and repair; however, whether DUSP3 affects these processes remains unknown. METHODS: Tumor cell lines in which DUSP3 activity was suppressed by pharmacological inhibitors or a targeted siRNA were exposed to gamma radiation, and proliferation, survival, DNA strand breaks and recombination repair pathways were sequentially analyzed. RESULTS: The combination of reduced DUSP3 activity and gamma irradiation resulted in decreased cellular proliferation and survival and increased cellular senescence compared with the effects of radiation exposure alone. Gamma radiation-induced DNA damage was increased by the loss of DUSP3 activity and correlated with increased levels of phospho-H2AX protein and numbers of ionizing radiation-induced γ-H2AX foci, which were reflected in diminished efficiencies of homologous recombination (HR) and non-homologous end-joining (NHEJ) repair. Similar results were obtained in ATM-deficient cells, in which reduced DUSP3 activity increased radiosensitivity, independent of increased MAPK phosphorylation. CONCLUSION: The loss of DUSP3 activity markedly increases gamma radiation-induced DNA strand breaks, suggesting a potential novel role for DUSP3 in DNA repair. GENERAL SIGNIFICANCE: The radioresistance of tumor cells is effectively reduced by a combination of approaches through the inhibition of DUSPs.

Immunohistochemical Jun/Fos protein localization and DNA synthesis in rat adrenal cortex after treatment with ACTH or FGF2.

In vitro and in vivo studies have suggested that the expression of the early response genes for Jun and Fos proteins plays an important role in adrenal cell proliferation. In order to study the expression pattern of the activating protein-1 (AP-1) family of oncogenes in the adrenal gland, we have used immunohistochemistry to localize Jun and Fos protein expression in rat adrenal cortex infused in situ with adrenocorticotropic hormone (ACTH), fibroblast growth factor 2 (FGF2), or both. The expression of AP-1 factors has been found to be correlated with in vivo ACTH and FGF2 proliferation in rats treated with dexamethasone and bromodeoxyuridine (BrdU). Induction of c-Jun and c-Fos in the zona fasciculata and of FosB in the zona reticularis suggests that, after ACTH stimulation, these proteins are the main AP-1 components in these zones. In vivo, ACTH increases BrdU-positive cells in the zona fasciculata and zona reticularis suggesting that the composition of AP-1 complexes in these zones is correlated with proliferation. Patterns of Fos and Jun induction by FGF2 do not resemble those after ACTH induction. However, in isolation, neither affects the zona glomerulosa. In the zona fasciculata, and more so in the zona reticularis, FGF2 modulates responses to ACTH, reducing the numbers of Jun-positive cells, Fos-positive cells, and DNA synthesis. This indicates that FGF2 antagonizes ACTH, and that ACTH thus controls the trophic effect independently of exogenous FGF2. Our results implicate the AP-1 family of transcription factors in the regulation of cell progression and the control of ACTH-induced proliferation in the zona fasciculata and zona reticularis.

To "do the right thing" or to "just do it": locomotion and assessment as distinct self-regulatory imperatives.

An integrated series of studies investigated 2 functional dimensions of self-regulation referred to as assessment and locomotion (E. T. Higgins and A. W. Kruglanski, 1995). Assessment constitutes the comparative aspect of self-regulation that critically evaluates alternative goals or means to decide which are best to pursue and appraises performance. Locomotion constitutes the aspect of self-regulation concerned with movement from state to state, including commitment of psychological resources to initiate and maintain such movement. Two separate scales were developed to measure individual differences in these tendencies. Psychometric work attested to the scales' unidimensionality, internal consistency, and temporal stability. The authors found that (a) locomotion and assessment are relatively independent of each other, (b) both are needed for self-regulatory success, and (c) each relates to distinct task orientations and motivational emphases.

Membership has its (epistemic) rewards: need for closure effects on in-group bias.

Three studies examined the impact of the need for cognitive closure on manifestations of in-group bias. All 3 studies found that high (vs. low) need for closure increased in-group favoritism and outgroup derogation. Specifically, Study 1 found a positive relation between need for cognitive closure and both participants' ethnic group identification and their collective self-esteem. Studies 2 and 3 found a positive relation between need for closure and participants' identification with an in-group member and their acceptance of an in-group member's beliefs and attitudes. Studies 2 and 3 also found a negative relation between need for closure and participants' identification with an out-group member and their acceptance of an out-group member's beliefs and attitudes. The implications of these findings for the epistemic function of in-groups are discussed.

Looking for truth in all the wrong places? Asymmetric search of individuating information about stereotyped group members.

Two experiments examined how category-based expectancies (CBEs) influence individuating information sought when trying to make accurate judgments about the attitudes of targets who were members of social categories that strongly or weakly implied the judged attitude. CBEs produced marked asymmetries in the number and content of participants' questions. Specifically, participants addressed fewer questions to stereotyped targets (STs) than to nonstereotyped targets (NSTs), thus acquiring relatively little individuating information about STs prior to judgement. Questions asked STs were diagnostically asymmetric-a response could better confirm than disconfirm the expected attitude, but questions to NSTs were diagnostically symmetric-a response could equally confirm or disconfirm the attitude. The authors discuss asymmetric search as a mechanism that may protect CBEs against disconfirmation independent of biased processing of acquired information.

Need for cognition and desire for control as moderators of extrinsic reward effects: a person x situation approach to the study of intrinsic motivation.

Seventy-four Ss in extrinsic-reward or no-reward conditions completed a brainstorming task and then were left alone with the option to engage in additional versions of this task. If the Need for Cognition (NFC) Scale taps intrinsic motivation for effortful cognition (J. T. Cacioppo & R. E. Petty, 1982), the optional task engagement of high-NFCSs, but not low-NFCSs, should be undermined by extrinsic reward. Results confirmed this hypothesis, but regression analyses showed that NFC scores' moderation of reward effects was due to their covariation with scores on J. M. Burger and H. M. Cooper's (1979) Desire for Control Scale. The data suggest that (a) NFC involves intrinsic motivation for effortful cognitive processing, (b) NFC may predict such processing mainly in contexts with minimal extrinsic incentives for processing, and (c) control motivation may be related causally both to extrinsic undermining effects and to individual differences in NFC.