We found that SphK2 KO MEFshad ancrease S1equvalent to WT MEFs whewe overexpressed AC,nonetheless SphK1 KO MEFshad no ncrease S1P, consstent wth thshypothess.The observatons ths research that AC promotes resstance to cytotoxc chemotherapes but senstvty to agents that target Akt demonstrate mportant dfferences with the dverse functons medated by AC.Aexceedngly commoand crtcal event cell death response to nonspec c stressors lke radatoand chemotherapy s the accumulatoof ceramde, whch actvates apoptoss through effectively characterzed mechansms.19,31 The ef cacy of cytotoxc chemotherapes ths and prevous studeshave beeshowto be lessened by expressoof AC, presumably by dampenng the accumulatoof ceramde and as a result downstream apoptotc sgnals.3 contrast, targeted nhbtoof Akt proves especally effectve cells overexpressng AC, ndcatng that AC overexpressng cancer cells, and hence potentally AC overexpressng tumors, are relant ooncogenc Akt actvatothrough the pathway de ned ths examine for ther oncogenc phenotypes.
Chemotherapy forhormone refractory prostate cancer s now lmted to Docetaxel, whch provdes mnmal bene t.32 Bopsy based mostly dagnostc strategies might be ready adapted for evaluatoof AC expressoand Akt actvaton, potentally nformng treatment Cilengitide concentration decsons the near potential as P3K and Akt nhbtors enter clncal use.Thus, whe AC contrbutes to death resstance the context of dverse cell stressors like radatoand chemotherapy by attenuatng ceramde accumulaton, the dent catoths examine of AC medated Akt actvatoprovdes crtcal nsght Alisertib nto spec c susceptbtes downstream of AC that could nform future clncal decsons.Akt sgnalng promotes prolferatondrectly by actvatng the mTOR pathway that controls translatoof peptdes required for cell growth, and drectly by phosphorylatng multple cycldependent knase nhbtors.33 Our study of the functonal consequences of AC nduced Akt sgnalng reveals 3 mportant observatons AC expressng cells prolferate more rapdly, AC promotes soft agar colony formatoand these oncogenc phenotypes are profoundly senstve to Akt nhbton.
That AC promotes cell prolferatos not surprsng, gvethe sgnalng mechansm outlned ths examine?Akt phosphorylates Wee1 and Myt1 the two of whch market mtotc entry by actvatng cdc2,34?36 and Akt drectly nactvates the cycldependent knase nhbtor p27kp1 whose nactvatoallows transtofrom G1 S.37 More nterestng s the ndng that AC overexpressng cells are far more senstve

to Akt nhbtowth regards to these functonal assays thaare controls cells.Ths ndcates that AC overexpressng cells not only relyheavy oAkt sgnalng for your development benefits ncurred by ncreased AC sgnalng, but also for ther baselne cell prolferatoand tumor formatopropertes, othe whole suggestng that AC expressocauses Akt sgnalng pathway addcton.