We noticed that SphK2 KO MEFshad ancrease S1equvalent to WT MEFs whewe overexpressed AC,however SphK1 KO MEFshad no ncrease S1P, consstent wth thshypothess.The observatons ths study that AC promotes resstance to cytotoxc chemotherapes but senstvty to agents that target Akt demonstrate mportant dfferences in the dverse functons medated by AC.Aexceedngly commoand crtcal occasion cell death response to nonspec c stressors lke radatoand chemotherapy s the accumulatoof ceramde, whch actvates apoptoss as a result of well 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 therefore downstream apoptotc sgnals.3 contrast, targeted nhbtoof Akt proves especally effectve cells overexpressng AC, ndcatng that AC overexpressng cancer cells, and consequently 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 presently lmted to Docetaxel, whch provdes mnmal bene t.32 Bopsy based dagnostc tactics could be ready adapted for evaluatoof AC expressoand Akt actvaton, potentally nformng remedy selelck kinase inhibitor decsons the near potential as P3K and Akt nhbtors enter clncal use.So, whe AC contrbutes to death resstance the context of dverse cell stressors just like radatoand chemotherapy by attenuatng ceramde accumulaton, the dent catoths review of AC medated Akt actvatoprovdes crtcal nsght YM201636 nto spec c susceptbtes downstream of AC that can nform potential clncal decsons.Akt sgnalng promotes prolferatondrectly by actvatng the mTOR pathway that controls translatoof peptdes vital for cell development, and drectly by phosphorylatng multple cycldependent knase nhbtors.33 Our research of your 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 review?Akt phosphorylates Wee1 and Myt1 the two of whch encourage mtotc entry by actvatng cdc2,34?36 and Akt drectly nactvates the cycldependent knase nhbtor p27kp1 whose nactvatoallows transtofrom G1 S.37 Much more nterestng s the ndng that AC overexpressng cells are extra senstve

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